ID DPOG1_HUMAN Reviewed; 1239 AA. AC P54098; Q8NFM2; Q92515; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 236. DE RecName: Full=DNA polymerase subunit gamma-1; DE EC=2.7.7.7 {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:9558343}; DE AltName: Full=3'-5' exodeoxyribonuclease; DE EC=3.1.11.- {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:9558343}; DE AltName: Full=5'-deoxyribose-phosphate lyase; DE EC=4.2.99.- {ECO:0000269|PubMed:9770471}; DE AltName: Full=Mitochondrial DNA polymerase catalytic subunit; DE AltName: Full=PolG-alpha; GN Name=POLG {ECO:0000303|PubMed:10827171, ECO:0000312|HGNC:HGNC:9179}; GN Synonyms=MDP1, POLG1 {ECO:0000303|PubMed:12707443}, POLGA; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND DOMAIN. RX PubMed=8884268; DOI=10.1006/geno.1996.0490; RA Ropp P.A., Copeland W.C.; RT "Cloning and characterization of the human mitochondrial DNA polymerase, RT DNA polymerase gamma."; RL Genomics 36:449-458(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9034326; DOI=10.1016/s0378-1119(96)00663-4; RA Lecrenier N.L., van der Bruggen P., Foury F.; RT "Mitochondrial DNA polymerases from yeast to man: a new family of RT polymerases."; RL Gene 185:147-152(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLN-GLN-55 INS. RC TISSUE=Brain; RA Watanabe T.K., Shimizu F., Nishino N., Fujiwara T., Kanemoto N., Suzuki M., RA Nakamura Y., Hirai Y., Maekawa H., Takahashi E.; RL Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-55 INS; GLN-193; RP CYS-546; LYS-662; TRP-1142; GLY-1143; CYS-1146 AND HIS-1236. RG NIEHS SNPs program; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9558343; DOI=10.1021/bi972685u; RA Graves S.W., Johnson A.A., Johnson K.A.; RT "Expression, purification, and initial kinetic characterization of the RT large subunit of the human mitochondrial DNA polymerase."; RL Biochemistry 37:6050-6058(1998). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9770471; DOI=10.1073/pnas.95.21.12244; RA Longley M.J., Prasad R., Srivastava D.K., Wilson S.H., Copeland W.C.; RT "Identification of 5'-deoxyribose phosphate lyase activity in human DNA RT polymerase gamma and its role in mitochondrial base excision repair in RT vitro."; RL Proc. Natl. Acad. Sci. U.S.A. 95:12244-12248(1998). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASP-198; ASP-890 AND ASP-1135. RX PubMed=10827171; DOI=10.1074/jbc.m000559200; RA Spelbrink J.N., Toivonen J.M., Hakkaart G.A., Kurkela J.M., Cooper H.M., RA Lehtinen S.K., Lecrenier N., Back J.W., Speijer D., Foury F., Jacobs H.T.; RT "In vivo functional analysis of the human mitochondrial DNA polymerase POLG RT expressed in cultured human cells."; RL J. Biol. Chem. 275:24818-24828(2000). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF GLU-200. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [12] RP REVIEW, AND DOMAIN. RX PubMed=15189144; DOI=10.1146/annurev.biochem.72.121801.161455; RA Kaguni L.S.; RT "DNA polymerase gamma, the mitochondrial replicase."; RL Annu. Rev. Biochem. 73:293-320(2004). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [14] RP SUBCELLULAR LOCATION, ASSOCIATION WITH MITOCHONDRIAL DNA, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=18063578; DOI=10.1074/jbc.m708444200; RA Bogenhagen D.F., Rousseau D., Burke S.; RT "The layered structure of human mitochondrial DNA nucleoids."; RL J. Biol. Chem. 283:3665-3675(2008). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-274, CHARACTERIZATION OF RP VARIANT LS HIS-232, CHARACTERIZATION OF VARIANTS PEOB1 ALA-268 AND ARG-304, RP AND CHARACTERIZATION OF VARIANTS GLN-275; LEU-277; ARG-303 AND ARG-305. RX PubMed=26095671; DOI=10.1038/ncomms8303; RA Macao B., Uhler J.P., Siibak T., Zhu X., Shi Y., Sheng W., Olsson M., RA Stewart J.B., Gustafsson C.M., Falkenberg M.; RT "The exonuclease activity of DNA polymerase gamma is required for ligation RT during mitochondrial DNA replication."; RL Nat. Commun. 6:7303-7303(2015). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [17] RP INTERACTION WITH TTC3. RX PubMed=29290964; DOI=10.18632/oncotarget.22476; RA Gong Y., Wang X., Shang X., Xiao S.P., Li W., Shang Y., Dou F.; RT "Tetratricopeptide repeat domain 3 overexpression tends to form aggregates RT and inhibit ubiquitination and degradation of DNA polymerase gamma."; RL Oncotarget 8:106475-106485(2017). RN [18] RP INTERACTION WITH LIG3. RX PubMed=33855352; DOI=10.1093/brain/awab056; RA Bonora E., Chakrabarty S., Kellaris G., Tsutsumi M., Bianco F., RA Bergamini C., Ullah F., Isidori F., Liparulo I., Diquigiovanni C., RA Masin L., Rizzardi N., Cratere M.G., Boschetti E., Papa V., Maresca A., RA Cenacchi G., Casadio R., Martelli P., Matera I., Ceccherini I., Fato R., RA Raiola G., Arrigo S., Signa S., Sementa A.R., Severino M., Striano P., RA Fiorillo C., Goto T., Uchino S., Oyazato Y., Nakamura H., Mishra S.K., RA Yeh Y.S., Kato T., Nozu K., Tanboon J., Morioka I., Nishino I., Toda T., RA Goto Y.I., Ohtake A., Kosaki K., Yamaguchi Y., Nonaka I., Iijima K., RA Mimaki M., Kurahashi H., Raams A., MacInnes A., Alders M., Engelen M., RA Linthorst G., de Koning T., den Dunnen W., Dijkstra G., van Spaendonck K., RA van Gent D.C., Aronica E.M., Picco P., Carelli V., Seri M., Katsanis N., RA Duijkers F.A.M., Taniguchi-Ikeda M., De Giorgio R.; RT "Biallelic variants in LIG3 cause a novel mitochondrial RT neurogastrointestinal encephalomyopathy."; RL Brain 144:1451-1466(2021). RN [19] RP X-RAY CRYSTALLOGRAPHY (3.24 ANGSTROMS) OF 70-1239, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, AND MUTAGENESIS OF 543-VAL--LEU-558; LEU-549; LEU-552 RP AND LYS-553. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [20] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 30-1239 IN COMPLEX WITH MG(2+); RP PRIMER-TEMPLATE; 2',3'-DIDEOXYCYTIDINE 5'-TRIPHOSPHATE AND INHIBITOR RP ZALCITABINE, COFACTOR, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, MUTAGENESIS OF LYS-498; LYS-499 AND LYS-501, AND DOMAIN. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [21] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS) IN COMPLEX WITH RP 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP ACTIVE SITE, SITE, AND MUTAGENESIS OF ASP-198; GLU-200 AND ARG-853. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [22] RP VARIANTS PEOB1 PRO-3; ARG-304; THR-467 AND CYS-955. RX PubMed=11431686; DOI=10.1038/90034; RA Van Goethem G., Dermaut B., Loefgren A., Martin J.-J., Van Broeckhoven C.; RT "Mutation of POLG is associated with progressive external ophthalmoplegia RT characterized by mtDNA deletions."; RL Nat. Genet. 28:211-212(2001). RN [23] RP VARIANTS PEOA1 ASP-923; HIS-943; CYS-955; SER-957 AND LEU-1176, AND RP VARIANTS PEOB1 ILE-251; LEU-309 AND SER-848. RX PubMed=12210792; DOI=10.1002/ana.10278; RA Lamantea E., Tiranti V., Bordoni A., Toscano A., Bono F., Servidei S., RA Papadimitriou A., Spelbrink H., Silvestri L., Casari G., Comi G.P., RA Zeviani M.; RT "Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of RT autosomal dominant or recessive progressive external ophthalmoplegia."; RL Ann. Neurol. 52:211-219(2002). RN [24] RP CHARACTERIZATION OF VARIANT PEOA1 CYS-955, FUNCTION, AND CATALYTIC RP ACTIVITY. RX PubMed=11897778; DOI=10.1074/jbc.c200100200; RA Ponamarev M.V., Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "Active site mutation in DNA polymerase gamma associated with progressive RT external ophthalmoplegia causes error-prone DNA synthesis."; RL J. Biol. Chem. 277:15225-15228(2002). RN [25] RP VARIANTS PEOB1 TRP-579; LEU-587; THR-889 AND VAL-1076, AND VARIANT RP HIS-1236. RX PubMed=12975295; DOI=10.1001/archneur.60.9.1279; RA Filosto M., Mancuso M., Nishigaki Y., Pancrudo J., Harati Y., Gooch C., RA Mankodi A., Bayne L., Bonilla E., Shanske S., Hirano M., DiMauro S.; RT "Clinical and genetic heterogeneity in progressive external ophthalmoplegia RT due to mutations in polymerase gamma."; RL Arch. Neurol. 60:1279-1284(2003). RN [26] RP VARIANTS MTDPS4B ILE-251; LEU-587 AND SER-864. RX PubMed=12825077; DOI=10.1038/sj.ejhg.5201002; RA Van Goethem G., Schwartz M., Loefgren A., Dermaut B., Van Broeckhoven C., RA Vissing J.; RT "Novel POLG mutations in progressive external ophthalmoplegia mimicking RT mitochondrial neurogastrointestinal encephalomyopathy."; RL Eur. J. Hum. Genet. 11:547-549(2003). RN [27] RP VARIANT PEOB1 SER-848. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [28] RP VARIANTS PEOB1 ILE-251; ALA-268; ARG-312; THR-467; GLN-562; LEU-587; RP PRO-807 AND TYR-932, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=14635118; DOI=10.1002/humu.9203; RA Di Fonzo A., Bordoni A., Crimi M., Sara G., Del Bo R., Bresolin N., RA Comi G.P.; RT "POLG mutations in sporadic mitochondrial disorders with multiple mtDNA RT deletions."; RL Hum. Mutat. 22:498-499(2003). RN [29] RP VARIANTS PEOB1 TRP-227; ILE-251; ARG-312; VAL-431; THR-467; GLN-1047; RP CYS-1096 AND CYS-1104. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [30] RP VARIANT SCAE THR-467. RX PubMed=14694057; DOI=10.1212/01.wnl.0000098997.23471.65; RA Van Goethem G., Mercelis R., Loefgren A., Seneca S., Ceuterick C., RA Martin J.-J., Van Broeckhoven C.; RT "Patient homozygous for a recessive POLG mutation presents with features of RT MERRF."; RL Neurology 61:1811-1813(2003). RN [31] RP VARIANTS SANDO PRO-3; ARG-304; THR-467; TRP-627 AND CYS-955. RX PubMed=12565911; DOI=10.1016/s0960-8966(02)00216-x; RA Van Goethem G., Martin J.-J., Dermaut B., Loefgren A., Wibail A., RA Ververken D., Tack P., Dehaene I., Van Zandijcke M., Moonen M., RA Ceuterick C., De Jonghe P., Van Broeckhoven C.; RT "Recessive POLG mutations presenting with sensory and ataxic neuropathy in RT compound heterozygote patients with progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 13:133-142(2003). RN [32] RP VARIANT MTDPS4A THR-467. RX PubMed=15122711; DOI=10.1002/ana.20079; RA Naviaux R.K., Nguyen K.V.; RT "POLG mutations associated with Alpers' syndrome and mitochondrial DNA RT depletion."; RL Ann. Neurol. 55:706-712(2004). RN [33] RP VARIANTS PEOB1 TRP-227; ILE-251; LEU-309; LEU-587; SER-848; ILE-1106 AND RP LEU-1176. RX PubMed=15349879; DOI=10.1002/ana.20219; RA Lamantea E., Zeviani M.; RT "Sequence analysis of familial PEO shows additional mutations associated RT with the 752C-->T and 3527C-->T changes in the POLG1 gene."; RL Ann. Neurol. 56:454-455(2004). RN [34] RP VARIANT PEOA1 CYS-831. RX PubMed=15534189; DOI=10.1001/archneur.61.11.1777; RA Mancuso M., Filosto M., Oh S.J., DiMauro S.; RT "A novel polymerase gamma mutation in a family with ophthalmoplegia, RT neuropathy, and parkinsonism."; RL Arch. Neurol. 61:1777-1779(2004). RN [35] RP VARIANTS PEOA1 CYS-953 AND CYS-955, AND VARIANTS PEOB1 ASP-468 AND RP THR-1105. RX PubMed=15351195; DOI=10.1016/s0140-6736(04)16983-3; RA Luoma P., Melberg A., Rinne J.O., Kaukonen J.A., Nupponen N.N., RA Chalmers R.M., Oldfors A., Rautakorpi I., Peltonen L., Majamaa K., RA Somer H., Suomalainen A.; RT "Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma RT mutations: clinical and molecular genetic study."; RL Lancet 364:875-882(2004). RN [36] RP VARIANTS SANDO TYR-932 AND ARG-1051. RX PubMed=14745080; DOI=10.1212/wnl.62.2.316; RA Mancuso M., Filosto M., Bellan M., Liguori R., Montagna P., Baruzzi A., RA DiMauro S., Carelli V.; RT "POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, RT ataxia, and deafness."; RL Neurology 62:316-318(2004). RN [37] RP VARIANT PEOB1 THR-467, VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=15477547; DOI=10.1212/01.wnl.0000140494.58732.83; RA Van Goethem G., Luoma P., Rantamaeki M., Al-Memar A., Kaakkola S., RA Hackman P., Krahe R., Loefgren A., Martin J.-J., De Jonghe P., RA Suomalainen A., Udd B., Van Broeckhoven C.; RT "POLG mutations in neurodegenerative disorders with ataxia but no muscle RT involvement."; RL Neurology 63:1251-1257(2004). RN [38] RP VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=16080118; DOI=10.1086/444548; RA Hakonen A.H., Heiskanen S., Juvonen V., Lappalainen I., Luoma P.T., RA Rantamaeki M., Van Goethem G., Loefgren A., Hackman P., Paetau A., RA Kaakkola S., Majamaa K., Varilo T., Udd B., Kaeaeriaeinen H., Bindoff L.A., RA Suomalainen A.; RT "Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal RT recessive ataxia with ancient European origin."; RL Am. J. Hum. Genet. 77:430-441(2005). RN [39] RP VARIANTS MTDPS4A SER-748 AND SER-848. RX PubMed=15929042; DOI=10.1002/ana.20498; RA Davidzon G., Mancuso M., Ferraris S., Quinzii C., Hirano M., Peters H.L., RA Kirby D., Thorburn D.R., DiMauro S.; RT "POLG mutations and Alpers syndrome."; RL Ann. Neurol. 57:921-923(2005). RN [40] RP VARIANTS MTDPS4A GLY-232; PRO-244; ILE-251; THR-467; LEU-587; SER-748; RP SER-848 AND PRO-957, AND VARIANT GLY-1143. RX PubMed=15689359; DOI=10.1093/brain/awh410; RA Ferrari G., Lamantea E., Donati A., Filosto M., Briem E., Carrara F., RA Parini R., Simonati A., Santer R., Zeviani M.; RT "Infantile hepatocerebral syndromes associated with mutations in the RT mitochondrial DNA polymerase-gammaA."; RL Brain 128:723-731(2005). RN [41] RP VARIANT PEOB1 THR-467, VARIANT SANDO GLN-627, VARIANT HIS-1236, RP CHARACTERIZATION OF VARIANT PEOB1 THR-467, CHARACTERIZATION OF VARIANT RP SANDO GLN-627, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15917273; DOI=10.1093/hmg/ddi196; RA Luoma P.T., Luo N., Loescher W.N., Farr C.L., Horvath R., Wanschitz J., RA Kiechl S., Kaguni L.S., Suomalainen A.; RT "Functional defects due to spacer-region mutations of human mitochondrial RT DNA polymerase in a family with an ataxia-myopathy syndrome."; RL Hum. Mol. Genet. 14:1907-1920(2005). RN [42] RP VARIANTS SANDO THR-467; HIS-497 AND SER-748. RX PubMed=15824347; DOI=10.1212/01.wnl.0000156516.77696.5a; RA Winterthun S., Ferrari G., He L., Taylor R.W., Zeviani M., Turnbull D.M., RA Engelsen B.A., Moen G., Bindoff L.A.; RT "Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial RT polymerase gamma mutations."; RL Neurology 64:1204-1208(2005). RN [43] RP VARIANTS PEOB1 ARG-737 AND TRP-853. RX PubMed=16634032; DOI=10.1002/ana.20831; RA Davidzon G., Greene P., Mancuso M., Klos K.J., Ahlskog J.E., Hirano M., RA DiMauro S.; RT "Early-onset familial parkinsonism due to POLG mutations."; RL Ann. Neurol. 59:859-862(2006). RN [44] RP VARIANTS PEOB1 LEU-603; TRP-853; CYS-1146 AND ASN-1184. RX PubMed=16401742; DOI=10.1001/archneur.63.1.107; RA Gonzalez-Vioque E., Blazquez A., Fernandez-Moreira D., Bornstein B., RA Bautista J., Arpa J., Navarro C., Campos Y., Fernandez-Moreno M.A., RA Garesse R., Arenas J., Martin M.A.; RT "Association of novel POLG mutations and multiple mitochondrial DNA RT deletions with variable clinical phenotypes in a Spanish population."; RL Arch. Neurol. 63:107-111(2006). RN [45] RP VARIANTS PEOB1 HIS-308; TRP-574 AND ARG-648, VARIANT SANDO VAL-517, AND RP VARIANTS MTDPS4A ASP-767; HIS-879; SER-885; PRO-914; HIS-1096 AND ASN-1191. RX PubMed=16621917; DOI=10.1093/brain/awl088; RA Horvath R., Hudson G., Ferrari G., Fuetterer N., Ahola S., Lamantea E., RA Prokisch H., Lochmueller H., McFarland R., Ramesh V., Klopstock T., RA Freisinger P., Salvi F., Mayr J.A., Santer R., Tesarova M., Zeman J., RA Udd B., Taylor R.W., Turnbull D., Hanna M., Fialho D., Suomalainen A., RA Zeviani M., Chinnery P.F.; RT "Phenotypic spectrum associated with mutations of the mitochondrial RT polymerase gamma gene."; RL Brain 129:1674-1684(2006). RN [46] RP VARIANTS PEOB1 ARG-304; ASP-380 AND THR-467, VARIANT SANDO SER-748, VARIANT RP MTDPS4A PRO-914, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [47] RP ERRATUM OF PUBMED:16639411. RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RL Eur. J. Hum. Genet. 15:607-607(2006). RN [48] RP VARIANTS SANDO ARG-648 AND CYS-807. RX PubMed=16919951; DOI=10.1016/j.nmd.2006.05.016; RA Gago M.F., Rosas M.J., Guimaraes J., Ferreira M., Vilarinho L., Castro L., RA Carpenter S.; RT "SANDO: two novel mutations in POLG1 gene."; RL Neuromuscul. Disord. 16:507-509(2006). RN [49] RP VARIANT PEOA1 ASN-511, AND VARIANT PHE-463. RX PubMed=17420318; DOI=10.1001/archneur.64.4.553; RA Hudson G., Schaefer A.M., Taylor R.W., Tiangyou W., Gibson A., Venables G., RA Griffiths P., Burn D.J., Turnbull D.M., Chinnery P.F.; RT "Mutation of the linker region of the polymerase gamma-1 (POLG1) gene RT associated with progressive external ophthalmoplegia and Parkinsonism."; RL Arch. Neurol. 64:553-557(2007). RN [50] RP VARIANT PEOA1 CYS-831. RX PubMed=17846414; DOI=10.1212/01.wnl.0000276955.23735.eb; RA Luoma P.T., Eerola J., Ahola S., Hakonen A.H., Hellstroem O., RA Kivistoe K.T., Tienari P.J., Suomalainen A.; RT "Mitochondrial DNA polymerase gamma variants in idiopathic sporadic RT Parkinson disease."; RL Neurology 69:1152-1159(2007). RN [51] RP VARIANT PEOA1 HIS-1186. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [52] RP VARIANTS LS HIS-232 AND SER-848, VARIANTS MTDPS4A ILE-251; THR-467; RP LEU-587; SER-748; CYS-831; SER-848; PRO-914; TYR-1110; ARG-1134 AND RP LYS-1136, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=18828154; DOI=10.1002/humu.20852; RA Taanman J.-W., Rahman S., Pagnamenta A.T., Morris A.A.M., RA Bitner-Glindzicz M., Wolf N.I., Leonard J.V., Clayton P.T., RA Schapira A.H.V.; RT "Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA RT depletion."; RL Hum. Mutat. 30:248-254(2009). RN [53] RP VARIANTS MTDPS4B TRP-227 AND SER-848. RX PubMed=19307547; DOI=10.1212/01.wnl.0000345002.47396.e1; RA Giordano C., Powell H., Leopizzi M., de Curtis M., Travaglini C., RA Sebastiani M., Gallo P., Taylor R.W., d'Amati G.; RT "Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to RT POLG1 mutations."; RL Neurology 72:1103-1105(2009). RN [54] RP VARIANTS SCAE THR-467 AND SER-748, AND VARIANTS MTDPS4A ARG-303; THR-467 RP AND SER-848. RX PubMed=20400524; DOI=10.1093/brain/awq067; RA Tzoulis C., Neckelmann G., Moerk S.J., Engelsen B.E., Viscomi C., Moen G., RA Ersland L., Zeviani M., Bindoff L.A.; RT "Localized cerebral energy failure in DNA polymerase gamma-associated RT encephalopathy syndromes."; RL Brain 133:1428-1437(2010). RN [55] RP VARIANTS PEOB1 LEU-277 AND CYS-943. RX PubMed=21301859; DOI=10.1007/s00415-011-5936-x; RA Sato K., Yabe I., Yaguchi H., Nakano F., Kunieda Y., Saitoh S., Sasaki H.; RT "Genetic analysis of two Japanese families with progressive external RT ophthalmoplegia and parkinsonism."; RL J. Neurol. 258:1327-1332(2011). RN [56] RP VARIANTS MTDPS4A ARG-305; THR-467; SER-748; SER-848; CYS-852 AND ARG-966. RX PubMed=22000311; DOI=10.1016/j.pediatrneurol.2011.07.008; RA Hunter M.F., Peters H., Salemi R., Thorburn D., Mackay M.T.; RT "Alpers syndrome with mutations in POLG: clinical and investigative RT features."; RL Pediatr. Neurol. 45:311-318(2011). RN [57] RP VARIANT MTDPS4A CYS-1096. RX PubMed=25129007; DOI=10.1007/s13312-014-0475-z; RA Bijarnia-Mahay S., Mohan N., Goyal D., Verma I.C.; RT "Mitochondrial DNA depletion syndrome causing liver failure."; RL Indian Pediatr. 51:666-668(2014). RN [58] RP INVOLVEMENT IN SCAE, AND VARIANTS SCAE THR-467; HIS-497 AND SER-748. RX PubMed=26942291; DOI=10.1016/j.ajhg.2016.01.009; RA Sandford E., Bird T.D., Li J.Z., Burmeister M.; RT "PRICKLE2 mutations might not be involved in epilepsy."; RL Am. J. Hum. Genet. 98:588-589(2016). RN [59] RP VARIANTS GLN-275 AND SER-848. RX PubMed=30552426; DOI=10.1038/s41431-018-0299-8; RA Papuc S.M., Abela L., Steindl K., Begemann A., Simmons T.L., Schmitt B., RA Zweier M., Oneda B., Socher E., Crowther L.M., Wohlrab G., Gogoll L., RA Poms M., Seiler M., Papik M., Baldinger R., Baumer A., Asadollahi R., RA Kroell-Seger J., Schmid R., Iff T., Schmitt-Mechelke T., Otten K., RA Hackenberg A., Addor M.C., Klein A., Azzarello-Burri S., Sticht H., RA Joset P., Plecko B., Rauch A.; RT "The role of recessive inheritance in early-onset epileptic RT encephalopathies: a combined whole-exome sequencing and copy number RT study."; RL Eur. J. Hum. Genet. 27:408-421(2019). CC -!- FUNCTION: Catalytic subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Replicates both heavy and CC light strands of the circular mtDNA genome using a single-stranded DNA CC template, RNA primers and the four deoxyribonucleoside triphosphates as CC substrates (PubMed:11477093, PubMed:11897778, PubMed:15917273, CC PubMed:19837034, PubMed:9558343). Has 5' -> 3' polymerase activity. CC Functionally interacts with TWNK and SSBP1 at the replication fork to CC form a highly processive replisome, where TWNK unwinds the double- CC stranded DNA template prior to replication and SSBP1 covers the CC parental heavy strand to enable continuous replication of the entire CC mitochondrial genome. A single nucleotide incorporation cycle includes CC binding of the incoming nucleotide at the insertion site, a CC phosphodiester bond formation reaction that extends the 3'-end of the CC primer DNA, and translocation of the primer terminus to the post- CC insertion site. After completing replication of a mtDNA strand, CC mediates 3' -> 5' exonucleolytic degradation at the nick to enable CC proper ligation (PubMed:11477093, PubMed:11897778, PubMed:15167897, CC PubMed:15917273, PubMed:19837034, PubMed:26095671, PubMed:9558343). CC Highly accurate due to high nucleotide selectivity and 3' -> 5' CC exonucleolytic proofreading. Proficiently corrects base substitutions, CC single-base additions and deletions in non-repetitive sequences and CC short repeats, but displays lower proofreading activity when CC replicating longer homopolymeric stretches. Exerts exonuclease activity CC toward single-stranded DNA and double-stranded DNA containing 3'- CC terminal mispairs. When a misincorporation occurs, transitions from CC replication to a pro-nucleolytic editing mode and removes the CC missincorporated nucleoside in the exonuclease active site. Proceeds CC via an SN2 nucleolytic mechanism in which Asp-198 catalyzes CC phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving CC group. As a result the primer strand becomes one nucleotide shorter and CC is positioned in the post-insertion site, ready to resume DNA synthesis CC (PubMed:10827171, PubMed:11477094, PubMed:11504725, PubMed:37202477). CC Exerts 5'-deoxyribose phosphate (dRP) lyase activity and mediates CC repair-associated mtDNA synthesis (gap filling) in base-excision repair CC pathway. Catalyzes the release of the 5'-terminal 2-deoxyribose-5- CC phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to CC produce a substrate for DNA ligase. The dRP lyase reaction does not CC require divalent metal ions and likely proceeds via a Schiff base CC intermediate in a beta-elimination reaction mechanism (PubMed:9770471). CC {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343, ECO:0000269|PubMed:9770471}. CC -!- CATALYTIC ACTIVITY: CC Reaction=DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + CC diphosphate; Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, Rhea:RHEA- CC COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:173112; CC EC=2.7.7.7; Evidence={ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:11477093, ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22509; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:37202477, ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 3'-end 2'-deoxyribonucleotidyl-deoxyribonucleotide-DNA + H2O CC = a 3'-end 2'-deoxyribonucleotide-DNA + a 2'-deoxyribonucleoside 5'- CC phosphate + H(+); Xref=Rhea:RHEA:77911, Rhea:RHEA-COMP:13863, CC Rhea:RHEA-COMP:19009, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:65317, ChEBI:CHEBI:138148, ChEBI:CHEBI:228185; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77912; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end 2'-deoxyribose-2'-deoxyribonucleotide-DNA = (2E,4S)- CC 4-hydroxypenten-2-al-5-phosphate + a 5'-end 5'-phospho-2'- CC deoxyribonucleoside-DNA + H(+); Xref=Rhea:RHEA:76255, Rhea:RHEA- CC COMP:13180, Rhea:RHEA-COMP:18657, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:136412, ChEBI:CHEBI:195194, ChEBI:CHEBI:195195; CC Evidence={ECO:0000269|PubMed:9770471}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76256; CC Evidence={ECO:0000269|PubMed:9770471}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:26056153}; CC -!- ACTIVITY REGULATION: Inhibited by dideoxynucleotides such as antiviral CC agent zalcitabine. {ECO:0000269|PubMed:26056153}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.011 uM for dTTP (POLG polymerase activity at matched G:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=0.015 uM for dTTP (POLG:POLG2 polymerase activity at matched G:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=7.6 uM for dTTP (POLG:POLG2 polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=10 uM for dTTP (POLG polymerase activity at mismatched T:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG:POLG2 polymerase activity at mismatched T:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=13 uM for dTTP (POLG polymerase activity at mismatched G:G primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched G:G CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=55 uM for dTTP (POLG polymerase activity at mismatched C:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched C:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2) (PubMed:11477093, PubMed:11477094, CC PubMed:15167897, PubMed:19837034, PubMed:26056153, PubMed:37202477). CC Interacts with TTC3 (PubMed:29290964). Interacts with LIG3 CC (PubMed:33855352). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC P54098; Q9UHN1: POLG2; NbExp=15; IntAct=EBI-852624, EBI-852642; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:18063578}. Mitochondrion matrix, mitochondrion CC nucleoid {ECO:0000269|PubMed:18063578}. CC -!- DOMAIN: The polymerase domain encompasses three conserved active site CC motifs: Pol A (residues 887-896), Pol B (residues 943-958) and Pol C CC (residues 1134-1141). Binds the incoming dNTPs and undergoes an open to CC close coformation change to catalyze the formation of phosphodiester CC bond. {ECO:0000269|PubMed:26056153, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The 3' -> 5' exonuclease domain comprises three conserved CC active site motifs: Exo I (residues 196-200), Exo II (residues 267-275) CC and Exo III (residues 395-403). Proofreads the newly synthesized DNA CC strand. {ECO:0000269|PubMed:37202477, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The trigger loop contracts to enable correctly matched primer- CC template pair entry into the polymerase domain and extends to preclude CC the mismatched one. {ECO:0000269|PubMed:37202477}. CC -!- DOMAIN: The accessory determinant domain (AID) interacts with POLG2 CC proximal monomer. {ECO:0000269|PubMed:26056153}. CC -!- POLYMORPHISM: The poly-Gln region seems to be polymorphic. CC {ECO:0000269|Ref.3, ECO:0000269|Ref.4}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 1 (PEOA1) [MIM:157640]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:12210792, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15534189, ECO:0000269|PubMed:17420318, CC ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18575922}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal recessive, 1 (PEOB1) [MIM:258450]: A severe form CC of progressive external ophthalmoplegia, a disorder characterized by CC progressive weakness of ocular muscles and levator muscle of the upper CC eyelid. It is clinically more heterogeneous than the autosomal dominant CC forms. {ECO:0000269|PubMed:11431686, ECO:0000269|PubMed:12210792, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12872260, CC ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, CC ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:16401742, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16634032, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:21301859, ECO:0000269|PubMed:26095671}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Sensory ataxic neuropathy dysarthria and ophthalmoparesis CC (SANDO) [MIM:607459]: A systemic disorder resulting from mitochondrial CC dysfunction associated with mitochondrial depletion in skeletal muscle CC and peripheral nerve tissue. The clinical triad of symptoms consists of CC sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, CC the phenotype varies widely, even within the same family, and can also CC include myopathy, seizures, and hearing loss. CC {ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:14745080, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15824347, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16080118, CC ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:16919951}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4A (MTDPS4A) CC [MIM:203700]: An autosomal recessive hepatocerebral syndrome due to CC mitochondrial dysfunction. The typical course of the disease includes CC severe developmental delay, intractable seizures, liver failure, and CC death in childhood. Refractory seizures, cortical blindness, CC progressive liver dysfunction, and acute liver failure after exposure CC to valproic acid are considered diagnostic features. The CC neuropathological hallmarks are neuronal loss, spongiform degeneration, CC and astrocytosis of the visual cortex. Liver biopsy results show CC steatosis, often progressing to cirrhosis. CC {ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15689359, CC ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:20400524, ECO:0000269|PubMed:22000311, CC ECO:0000269|PubMed:25129007}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4B (MTDPS4B) CC [MIM:613662]: An autosomal recessive progressive multisystem disorder CC due to mitochondrial dysfunction. It is clinically characterized by CC chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, CC progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, CC and muscle weakness. {ECO:0000269|PubMed:12825077, CC ECO:0000269|PubMed:19307547}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive CC neurodegenerative disorder characterized by the presence of focal, CC bilateral lesions in one or more areas of the central nervous system CC including the brainstem, thalamus, basal ganglia, cerebellum and spinal CC cord. Clinical features depend on which areas of the central nervous CC system are involved and include subacute onset of psychomotor CC retardation, hypotonia, ataxia, weakness, vision loss, eye movement CC abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:26095671}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spinocerebellar ataxia with epilepsy (SCAE) [MIM:607459]: An CC autosomal recessive syndrome characterized by headaches and/or seizures CC manifesting in childhood or adolescence, cerebellar and sensory ataxia, CC dysarthria, and myoclonus manifesting in early adulthood. CC Neuropathological findings include spinocerebellar degeneration CC associated with cortical neuronal degeneration in advanced cases. CC {ECO:0000269|PubMed:14694057, ECO:0000269|PubMed:20400524, CC ECO:0000269|PubMed:26942291}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the DNA polymerase type-A family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U60325; AAC50712.1; -; mRNA. DR EMBL; X98093; CAA66719.1; -; mRNA. DR EMBL; D84103; BAA12223.1; -; mRNA. DR EMBL; AF497906; AAM77583.1; -; Genomic_DNA. DR EMBL; BC042571; AAH42571.1; -; mRNA. DR EMBL; BC050559; AAH50559.1; -; mRNA. DR CCDS; CCDS10350.1; -. DR PIR; G02750; G02750. DR RefSeq; NP_001119603.1; NM_001126131.2. DR RefSeq; NP_002684.1; NM_002693.3. DR PDB; 3IKM; X-ray; 3.24 A; A/D=70-1239. DR PDB; 4ZTU; X-ray; 3.30 A; A=30-1239. DR PDB; 4ZTZ; X-ray; 3.44 A; A=30-1239. DR PDB; 5C51; X-ray; 3.43 A; A=25-1239. DR PDB; 5C52; X-ray; 3.64 A; A=25-1239. DR PDB; 5C53; X-ray; 3.57 A; A=25-1239. DR PDB; 8D33; EM; 2.46 A; A=1-1239. DR PDB; 8D37; EM; 2.65 A; A=1-1239. DR PDB; 8D3R; EM; 3.04 A; A=1-1239. DR PDB; 8D42; EM; 2.91 A; A=1-1239. DR PDB; 8G5I; EM; 2.75 A; A=1-1239. DR PDB; 8G5J; EM; 2.63 A; A=1-1239. DR PDB; 8G5K; EM; 2.90 A; A=1-1239. DR PDB; 8G5L; EM; 3.00 A; A=1-1239. DR PDB; 8G5M; EM; 2.58 A; A=1-1239. DR PDB; 8G5N; EM; 2.73 A; A=1-1239. DR PDB; 8G5O; EM; 2.61 A; A=1-1239. DR PDB; 8G5P; EM; 2.78 A; A=1-1239. DR PDB; 8T7E; EM; 3.08 A; A=1-1239. DR PDB; 8UDK; X-ray; 3.43 A; A=1-1239. DR PDB; 8UDL; EM; 2.37 A; A=1-1239. DR PDB; 8V54; EM; 4.10 A; A=26-1239. DR PDB; 8V55; EM; 4.20 A; A=26-1239. DR PDB; 8V5D; EM; 3.00 A; A=26-1239. DR PDB; 8V5R; EM; 3.00 A; A=26-1239. DR PDB; 9GGB; EM; 2.63 A; A=26-1239. DR PDB; 9GGC; EM; 2.39 A; A=26-1239. DR PDB; 9GGD; EM; 2.67 A; A=26-1239. DR PDB; 9GGE; EM; 2.69 A; A=26-1239. DR PDB; 9GGF; EM; 2.65 A; A=26-1239. DR PDB; 9IC1; EM; 2.73 A; A=26-1239. DR PDB; 9IC3; EM; 2.96 A; A=26-1239. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5D; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IC1; -. DR PDBsum; 9IC3; -. DR AlphaFoldDB; P54098; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42982; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52824; -. DR EMDB; EMD-52828; -. DR SMR; P54098; -. DR BioGRID; 111424; 116. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; P54098; 1006. DR IntAct; P54098; 64. DR MINT; P54098; -. DR STRING; 9606.ENSP00000399851; -. DR BindingDB; P54098; -. DR ChEMBL; CHEMBL2732; -. DR DrugBank; DB12151; Brincidofovir. DR DrugCentral; P54098; -. DR GlyGen; P54098; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P54098; -. DR PhosphoSitePlus; P54098; -. DR SwissPalm; P54098; -. DR BioMuta; POLG; -. DR DMDM; 1706507; -. DR jPOST; P54098; -. DR MassIVE; P54098; -. DR PaxDb; 9606-ENSP00000268124; -. DR PeptideAtlas; P54098; -. DR ProteomicsDB; 56642; -. DR Pumba; P54098; -. DR Antibodypedia; 28558; 222 antibodies from 35 providers. DR DNASU; 5428; -. DR Ensembl; ENST00000268124.11; ENSP00000268124.5; ENSG00000140521.18. DR Ensembl; ENST00000442287.6; ENSP00000399851.2; ENSG00000140521.18. DR Ensembl; ENST00000636937.2; ENSP00000516154.1; ENSG00000140521.18. DR GeneID; 5428; -. DR KEGG; hsa:5428; -. DR MANE-Select; ENST00000268124.11; ENSP00000268124.5; NM_002693.3; NP_002684.1. DR UCSC; uc002bnr.5; human. DR AGR; HGNC:9179; -. DR ClinPGx; PA33500; -. DR CTD; 5428; -. DR DisGeNET; 5428; -. DR GeneCards; POLG; -. DR GeneReviews; POLG; -. DR HGNC; HGNC:9179; POLG. DR HPA; ENSG00000140521; Low tissue specificity. DR MalaCards; POLG; -. DR MIM; 157640; phenotype. DR MIM; 174763; gene. DR MIM; 203700; phenotype. DR MIM; 256000; phenotype. DR MIM; 258450; phenotype. DR MIM; 607459; phenotype. DR MIM; 613662; phenotype. DR OpenTargets; ENSG00000140521; -. DR Orphanet; 726; Alpers-Huttenlocher syndrome. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 254886; Autosomal recessive progressive external ophthalmoplegia. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR Orphanet; 402082; Progressive myoclonic epilepsy type 5. DR Orphanet; 94125; Recessive mitochondrial ataxia syndrome. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR Orphanet; 254881; Spinocerebellar ataxia with epilepsy. DR VEuPathDB; HostDB:ENSG00000140521; -. DR eggNOG; KOG3657; Eukaryota. DR GeneTree; ENSGT00390000000453; -. DR HOGENOM; CLU_001524_2_2_1; -. DR InParanoid; P54098; -. DR OMA; AMHITNL; -. DR OrthoDB; 5588663at2759; -. DR PAN-GO; P54098; 4 GO annotations based on evolutionary models. DR PhylomeDB; P54098; -. DR PathwayCommons; P54098; -. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; P54098; -. DR SIGNOR; P54098; -. DR Agora; ENSG00000140521; -. DR BioGRID-ORCS; 5428; 224 hits in 1160 CRISPR screens. DR ChiTaRS; POLG; human. DR GeneWiki; POLG; -. DR GenomeRNAi; 5428; -. DR Pharos; P54098; Tchem. DR PRO; PR:P54098; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; P54098; protein. DR Bgee; ENSG00000140521; Expressed in granulocyte and 212 other cell types or tissues. DR ExpressionAtlas; P54098; baseline and differential. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:FlyBase. DR GO; GO:0051575; F:5'-deoxyribose-5-phosphate lyase activity; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IDA:UniProtKB. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0008310; F:single-stranded DNA 3'-5' DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0006284; P:base-excision repair; IDA:UniProtKB. DR GO; GO:0006287; P:base-excision repair, gap-filling; IDA:MGI. DR GO; GO:0006259; P:DNA metabolic process; TAS:ProtInc. DR GO; GO:0045004; P:DNA replication proofreading; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR CDD; cd08641; DNA_pol_gammaA; 1. DR FunFam; 1.10.150.20:FF:000024; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 1.20.5.3960:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000001; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR Gene3D; 1.20.5.3960; -; 1. DR Gene3D; 3.30.420.390; -; 2. DR Gene3D; 3.30.70.370; -; 1. DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1. DR InterPro; IPR019760; DNA-dir_DNA_pol_A_CS. DR InterPro; IPR002297; DNA-dir_DNA_pol_A_mt. DR InterPro; IPR001098; DNA-dir_DNA_pol_A_palm_dom. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR041336; DNApol_Exo. DR InterPro; IPR047580; POLG_palm_dom. DR InterPro; IPR012337; RNaseH-like_sf. DR PANTHER; PTHR10267; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR PANTHER; PTHR10267:SF0; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR Pfam; PF18136; DNApol_Exo; 1. DR PIRSF; PIRSF000797; DNA_pol_mt; 1. DR PRINTS; PR00867; DNAPOLG. DR SMART; SM00482; POLAc; 1. DR SUPFAM; SSF56672; DNA/RNA polymerases; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR PROSITE; PS00447; DNA_POLYMERASE_A; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; KW DNA-directed DNA polymerase; Epilepsy; Hydrolase; Leigh syndrome; Lyase; KW Magnesium; Mitochondrion; Mitochondrion nucleoid; Neurodegeneration; KW Neuropathy; Nucleotidyltransferase; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transferase. FT CHAIN 1..1239 FT /note="DNA polymerase subunit gamma-1" FT /id="PRO_0000101270" FT REGION 1..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 43..55 FT /note="Does not contribute to polymerase and exonuclease FT enzymatic activities" FT /evidence="ECO:0000269|PubMed:10827171" FT REGION 318..340 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 506..531 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 510..571 FT /note="Accessory-interacting determinant" FT /evidence="ECO:0000269|PubMed:26056153" FT REGION 858..864 FT /note="Trigger loop" FT /evidence="ECO:0000269|PubMed:37202477" FT MOTIF 196..200 FT /note="Exo I" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 267..275 FT /note="Exo II" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 395..403 FT /note="Exo III" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 887..896 FT /note="Pol A" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 943..958 FT /note="Pol B" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 1134..1141 FT /note="Pol C" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT COMPBIAS 9..36 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 44..60 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 198 FT /note="Exonuclease activity" FT /evidence="ECO:0000269|PubMed:37202477" FT BINDING 306 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 579 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 593 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 754 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 763 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 768 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 806 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 849 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 863 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 869 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 891 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 891 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 893 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 895 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 943 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 947 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 951 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1094 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1095 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT SITE 853 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT SITE 1102 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT VARIANT 3 FT /note="R -> P (in PEOB1 and SANDO; dbSNP:rs121918045)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911" FT /id="VAR_012153" FT VARIANT 18 FT /note="P -> S (in dbSNP:rs3087373)" FT /id="VAR_014904" FT VARIANT 55 FT /note="Q -> QQ" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019265" FT VARIANT 55 FT /note="Q -> QQQ" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_019266" FT VARIANT 193 FT /note="R -> Q (in dbSNP:rs3176162)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019267" FT VARIANT 227 FT /note="R -> W (in PEOB1 and MTDPS4B; dbSNP:rs121918056)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:19307547" FT /id="VAR_023663" FT VARIANT 232 FT /note="R -> G (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058870" FT VARIANT 232 FT /note="R -> H (in LS; displays markedly increased FT exonuclease activity and reduced polymerization activity; FT produces ligatable 5'-ends; dbSNP:rs113994093)" FT /evidence="ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058871" FT VARIANT 244 FT /note="L -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058872" FT VARIANT 251 FT /note="T -> I (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994094)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:18828154" FT /id="VAR_023664" FT VARIANT 268 FT /note="G -> A (in PEOB1; sporadic case; displays mildly FT reduced exonuclease activity; does not affect the FT polymerization activity or 5'-end ligation; FT dbSNP:rs61752784)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058873" FT VARIANT 275 FT /note="R -> Q (found in a patient with epileptic FT encephalopathy, developmental delay and moderate FT intellectual disability; uncertain significance; displays FT mildly reduced exonuclease activity; reduced polymerization FT activity; reduced DNA-binding affinity; does not affect 5'- FT end ligation; dbSNP:rs1555453950)" FT /evidence="ECO:0000269|PubMed:26095671, FT ECO:0000269|PubMed:30552426" FT /id="VAR_088657" FT VARIANT 277 FT /note="H -> L (in PEOB1; uncertain significance; does not FT affect exonuclease activity; does not affect polymerization FT activity; does not affect 5'-end ligation; FT dbSNP:rs138929605)" FT /evidence="ECO:0000269|PubMed:21301859, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088658" FT VARIANT 303 FT /note="G -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs749799663)" FT /evidence="ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088659" FT VARIANT 304 FT /note="L -> R (in PEOB1 and SANDO; results in loss of FT exonuclease activity and formation of an unligatable 5'- FT flap; displays low polymerization activity and reduced DNA- FT binding affinity; dbSNP:rs121918044)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:26095671" FT /id="VAR_012154" FT VARIANT 304 FT /note="L -> SANDO (in PEOB1)" FT /id="VAR_058874" FT VARIANT 305 FT /note="S -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs769410130)" FT /evidence="ECO:0000269|PubMed:22000311, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088660" FT VARIANT 308 FT /note="Q -> H (in PEOB1; sporadic case; dbSNP:rs745539599)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058875" FT VARIANT 309 FT /note="R -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023665" FT VARIANT 312 FT /note="W -> R (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118" FT /id="VAR_023666" FT VARIANT 324 FT /note="P -> S (in dbSNP:rs2307437)" FT /id="VAR_014905" FT VARIANT 380 FT /note="G -> D (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16639411" FT /id="VAR_058876" FT VARIANT 431 FT /note="G -> V (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023667" FT VARIANT 463 FT /note="L -> F (in dbSNP:rs150828914)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058877" FT VARIANT 467 FT /note="A -> T (in PEOB1, SANDO, SCAE and MTDPS4A; FT pathogenic; results in clearly decreased activity, DNA FT binding and processivity of the polymerase; FT dbSNP:rs113994095)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:14694057, FT ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15689359, ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_012155" FT VARIANT 468 FT /note="N -> D (in PEOB1; dbSNP:rs145843073)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023668" FT VARIANT 497 FT /note="Q -> H (in SANDO and SCAE; dbSNP:rs121918052)" FT /evidence="ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:26942291" FT /id="VAR_023669" FT VARIANT 511 FT /note="S -> N (in PEOA1; dbSNP:rs121918055)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058878" FT VARIANT 517 FT /note="G -> V (in SANDO; dbSNP:rs61752783)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058879" FT VARIANT 546 FT /note="R -> C (in dbSNP:rs2307447)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014906" FT VARIANT 562 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs781168350)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058880" FT VARIANT 574 FT /note="R -> W (in PEOB1; sporadic case; dbSNP:rs774474723)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058881" FT VARIANT 579 FT /note="R -> W (in PEOB1; dbSNP:rs556925652)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023670" FT VARIANT 587 FT /note="P -> L (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994096)" FT /evidence="ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:18828154" FT /id="VAR_023671" FT VARIANT 603 FT /note="M -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058882" FT VARIANT 627 FT /note="R -> Q (in SANDO; shows DNA binding affinity and FT processivities similar to the controls; dbSNP:rs375305567)" FT /evidence="ECO:0000269|PubMed:15917273" FT /id="VAR_058883" FT VARIANT 627 FT /note="R -> W (in SANDO; sporadic case; dbSNP:rs121918046)" FT /evidence="ECO:0000269|PubMed:12565911" FT /id="VAR_023672" FT VARIANT 648 FT /note="P -> R (in PEOB1; sporadic case; also in SANDO; FT dbSNP:rs796052906)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16919951" FT /id="VAR_058884" FT VARIANT 662 FT /note="E -> K (in dbSNP:rs2307450)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014907" FT VARIANT 737 FT /note="G -> R (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918054)" FT /evidence="ECO:0000269|PubMed:16634032" FT /id="VAR_058885" FT VARIANT 748 FT /note="W -> S (in SANDO, SCAE and MTDPS4A; pathogenic; FT dbSNP:rs113994097)" FT /evidence="ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15824347, ECO:0000269|PubMed:15929042, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_023673" FT VARIANT 767 FT /note="A -> D (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058886" FT VARIANT 807 FT /note="R -> C (in SANDO; dbSNP:rs769827124)" FT /evidence="ECO:0000269|PubMed:16919951" FT /id="VAR_058887" FT VARIANT 807 FT /note="R -> P (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058888" FT VARIANT 831 FT /note="Y -> C (in PEOA1 and MTDPS4A; uncertain FT significance; dbSNP:rs41549716)" FT /evidence="ECO:0000269|PubMed:15534189, FT ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18828154" FT /id="VAR_023674" FT VARIANT 848 FT /note="G -> S (in PEOB1, MTDPS4A, MTDPS4B and LS; also FT found in a patient with epileptic encephalopathy, FT developmental delay and moderate intellectual disability; FT dbSNP:rs113994098)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:19307547, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:30552426" FT /id="VAR_023675" FT VARIANT 852 FT /note="R -> C (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088688" FT VARIANT 853 FT /note="R -> W (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918053)" FT /evidence="ECO:0000269|PubMed:16401742, FT ECO:0000269|PubMed:16634032" FT /id="VAR_058889" FT VARIANT 864 FT /note="N -> S (in MTDPS4B; dbSNP:rs121918050)" FT /evidence="ECO:0000269|PubMed:12825077" FT /id="VAR_023676" FT VARIANT 879 FT /note="Q -> H (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058890" FT VARIANT 885 FT /note="T -> S (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058891" FT VARIANT 889 FT /note="A -> T (in PEOB1; dbSNP:rs763393580)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023677" FT VARIANT 914 FT /note="T -> P (in MTDPS4A; dbSNP:rs139590686)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154" FT /id="VAR_058892" FT VARIANT 923 FT /note="G -> D (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023678" FT VARIANT 932 FT /note="H -> Y (in SANDO and PEOB1; sporadic case; FT dbSNP:rs121918048)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:14745080" FT /id="VAR_023679" FT VARIANT 943 FT /note="R -> C (in PEOB1; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:21301859" FT /id="VAR_088689" FT VARIANT 943 FT /note="R -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023680" FT VARIANT 953 FT /note="R -> C (in PEOA1; dbSNP:rs11546842)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023681" FT VARIANT 955 FT /note="Y -> C (in PEOA1, PEOB1 and SANDO; 45-fold decrease FT in apparent binding affinity for the incoming nucleoside FT triphosphate; 2-fold less accurate for basepair FT substitutions than wild-type; dbSNP:rs113994099)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:15351195" FT /id="VAR_012156" FT VARIANT 957 FT /note="A -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058893" FT VARIANT 957 FT /note="A -> S (in PEOA1; dbSNP:rs121918051)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023682" FT VARIANT 966 FT /note="L -> R (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088690" FT VARIANT 1047 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs768028281)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023683" FT VARIANT 1051 FT /note="G -> R (in SANDO; dbSNP:rs121918049)" FT /evidence="ECO:0000269|PubMed:14745080" FT /id="VAR_023684" FT VARIANT 1076 FT /note="G -> V (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023685" FT VARIANT 1096 FT /note="R -> C (in PEOB1 and MTDPS4A; dbSNP:rs201732356)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:25129007" FT /id="VAR_023686" FT VARIANT 1096 FT /note="R -> H (in MTDPS4A; dbSNP:rs368435864)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058894" FT VARIANT 1104 FT /note="S -> C (in PEOB1; sporadic case; FT dbSNP:rs1010372555)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023687" FT VARIANT 1105 FT /note="A -> T (in PEOB1; dbSNP:rs753410045)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023688" FT VARIANT 1106 FT /note="V -> I (in PEOB1)" FT /evidence="ECO:0000269|PubMed:15349879" FT /id="VAR_023689" FT VARIANT 1110 FT /note="H -> Y (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058895" FT VARIANT 1134 FT /note="H -> R (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058896" FT VARIANT 1136 FT /note="E -> K (in MTDPS4A; dbSNP:rs56047213)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_065092" FT VARIANT 1142 FT /note="R -> W (in dbSNP:rs2307442)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014908" FT VARIANT 1143 FT /note="E -> G (in dbSNP:rs2307441)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|Ref.4" FT /id="VAR_014909" FT VARIANT 1146 FT /note="R -> C (in PEOB1; uncertain significance; FT dbSNP:rs2307440)" FT /evidence="ECO:0000269|PubMed:16401742, ECO:0000269|Ref.4" FT /id="VAR_014910" FT VARIANT 1176 FT /note="S -> L (in PEOA1; dbSNP:rs776031396)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023690" FT VARIANT 1184 FT /note="D -> N (in PEOB1; dbSNP:rs1131691575)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058897" FT VARIANT 1186 FT /note="D -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065119" FT VARIANT 1191 FT /note="K -> N (in MTDPS4A; dbSNP:rs1085307741)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058898" FT VARIANT 1236 FT /note="Q -> H (in dbSNP:rs3087374)" FT /evidence="ECO:0000269|PubMed:12975295, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:15917273, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, FT ECO:0000269|Ref.4" FT /id="VAR_014911" FT MUTAGEN 198 FT /note="D->A: Abolishes exonuclease activity; when FT associated with A-200. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-200. FT Significantly increases mitochondrial DNA mutation FT frequency. Does not affect DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 200 FT /note="E->A: Abolishes exonuclease activity; when FT associated with A-198. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-198." FT /evidence="ECO:0000269|PubMed:11477093, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 274 FT /note="D->A: Unable to idle at the 5'-end of the nascent FT DNA strand. Continues DNA synthesis into double-stranded FT DNA past the 5'-end creating a flap structure that cannot FT be ligated." FT /evidence="ECO:0000269|PubMed:26095671" FT MUTAGEN 498 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 499 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 501 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 543..558 FT /note="Missing: Markedly decreases the stimulation by FT POLG2, resulting in impaired processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 549 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 552 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 553 FT /note="K->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 853 FT /note="R->A: Abolishes primer DNA extention in the presence FT of dNTPs. Impairs intrinsic polymerase processivity. FT Enhances exonuclease activity leading to primer DNA FT degradation." FT /evidence="ECO:0000269|PubMed:37202477" FT MUTAGEN 890 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT MUTAGEN 1135 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT HELIX 73..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 81..87 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 97..110 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 135..157 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 172..178 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 180..182 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 184..186 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 193..200 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 203..205 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 207..210 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 211..215 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 220..224 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 226..229 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 237..239 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 241..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..251 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 260..262 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 279..282 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 283..285 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 290..293 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 294..300 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 306..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 347..350 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 356..363 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 376..379 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 382..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 389..417 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 421..430 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 435..438 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 440..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..481 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 483..487 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:5C51" FT STRAND 519..521 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 538..553 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 554..558 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 559..561 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 567..569 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 571..575 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 587..589 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 594..598 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 599..602 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 606..609 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 610..615 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 616..618 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 619..624 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 628..630 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 636..644 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 648..650 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 651..662 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 716..721 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 739..742 FT /evidence="ECO:0007829|PDB:8D3R" FT STRAND 743..745 FT /evidence="ECO:0007829|PDB:4ZTU" FT STRAND 748..751 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 755..757 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 765..767 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 768..770 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 771..775 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 778..780 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 782..784 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 787..809 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 814..816 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 818..820 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 823..826 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 833..835 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 837..840 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 845..848 FT /evidence="ECO:0007829|PDB:4ZTU" FT TURN 849..851 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 853..855 FT /evidence="ECO:0007829|PDB:4ZTU" FT HELIX 859..861 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 867..869 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 872..877 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 884..890 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 894..907 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 909..911 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 915..922 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 925..928 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 931..938 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 943..954 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 959..969 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 971..973 FT /evidence="ECO:0007829|PDB:8V5D" FT HELIX 975..989 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 991..993 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 997..999 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1001..1009 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1010..1013 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1027..1030 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1033..1035 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1037..1040 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 1041..1046 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1050..1052 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1055..1066 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1067..1069 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1073..1075 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1081..1083 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1085..1087 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1089..1092 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 1093..1122 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1127..1132 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1134..1142 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1143..1145 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1146..1167 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1175..1177 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1183..1188 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1191..1194 FT /evidence="ECO:0007829|PDB:8D33" FT STRAND 1202..1204 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 1206..1209 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1216..1218 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1220..1227 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1232..1235 FT /evidence="ECO:0007829|PDB:3IKM" SQ SEQUENCE 1239 AA; 139562 MW; 2D9ECCD75AD6E01E CRC64; MSRLLWRKVA GATVGPGPVP APGRWVSSSV PASDPSDGQR RRQQQQQQQQ QQQQQPQQPQ VLSSEGGQLR HNPLDIQMLS RGLHEQIFGQ GGEMPGEAAV RRSVEHLQKH GLWGQPAVPL PDVELRLPPL YGDNLDQHFR LLAQKQSLPY LEAANLLLQA QLPPKPPAWA WAEGWTRYGP EGEAVPVAIP EERALVFDVE VCLAEGTCPT LAVAISPSAW YSWCSQRLVE ERYSWTSQLS PADLIPLEVP TGASSPTQRD WQEQLVVGHN VSFDRAHIRE QYLIQGSRMR FLDTMSMHMA ISGLSSFQRS LWIAAKQGKH KVQPPTKQGQ KSQRKARRGP AISSWDWLDI SSVNSLAEVH RLYVGGPPLE KEPRELFVKG TMKDIRENFQ DLMQYCAQDV WATHEVFQQQ LPLFLERCPH PVTLAGMLEM GVSYLPVNQN WERYLAEAQG TYEELQREMK KSLMDLANDA CQLLSGERYK EDPWLWDLEW DLQEFKQKKA KKVKKEPATA SKLPIEGAGA PGDPMDQEDL GPCSEEEEFQ QDVMARACLQ KLKGTTELLP KRPQHLPGHP GWYRKLCPRL DDPAWTPGPS LLSLQMRVTP KLMALTWDGF PLHYSERHGW GYLVPGRRDN LAKLPTGTTL ESAGVVCPYR AIESLYRKHC LEQGKQQLMP QEAGLAEEFL LTDNSAIWQT VEELDYLEVE AEAKMENLRA AVPGQPLALT ARGGPKDTQP SYHHGNGPYN DVDIPGCWFF KLPHKDGNSC NVGSPFAKDF LPKMEDGTLQ AGPGGASGPR ALEINKMISF WRNAHKRISS QMVVWLPRSA LPRAVIRHPD YDEEGLYGAI LPQVVTAGTI TRRAVEPTWL TASNARPDRV GSELKAMVQA PPGYTLVGAD VDSQELWIAA VLGDAHFAGM HGCTAFGWMT LQGRKSRGTD LHSKTATTVG ISREHAKIFN YGRIYGAGQP FAERLLMQFN HRLTQQEAAE KAQQMYAATK GLRWYRLSDE GEWLVRELNL PVDRTEGGWI SLQDLRKVQR ETARKSQWKK WEVVAERAWK GGTESEMFNK LESIATSDIP RTPVLGCCIS RALEPSAVQE EFMTSRVNWV VQSSAVDYLH LMLVAMKWLF EEFAIDGRFC ISIHDEVRYL VREEDRYRAA LALQITNLLT RCMFAYKLGL NDLPQSVAFF SAVDIDRCLR KEVTMDCKTP SNPTGMERRY GIPQGEALDI YQIIELTKGS LEKRSQPGP // ID ZNT10_HUMAN Reviewed; 485 AA. AC Q6XR72; Q49AL9; Q9NPW0; DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 28-JAN-2026, entry version 156. DE RecName: Full=Calcium/manganese antiporter SLC30A10 {ECO:0000305|PubMed:30755481}; DE AltName: Full=Solute carrier family 30 member 10 {ECO:0000312|HGNC:HGNC:25355}; DE AltName: Full=Zinc transporter 10; DE Short=ZnT-10; GN Name=SLC30A10 {ECO:0000312|HGNC:HGNC:25355}; GN Synonyms=ZNT10 {ECO:0000303|PubMed:22706290}, ZNT8 {ECO:0000303|Ref.1}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Huang L., Zhou B., Gitschier J.; RT "Characterization of a novel mammalian zinc transporter, ZNT8."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 90-485 (ISOFORM 3). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP TISSUE SPECIFICITY. RX PubMed=15154973; DOI=10.1186/1471-2164-5-32; RA Seve M., Chimienti F., Devergnas S., Favier A.; RT "In silico identification and expression of SLC30 family genes: an RT expressed sequence tag data mining strategy for the characterization of RT zinc transporters' tissue expression."; RL BMC Genomics 5:32-32(2004). RN [6] RP FUNCTION, INVOLVEMENT IN HMNDYT1, VARIANTS HMNDYT1 PRO-89; 105-ALA--PRO-107 RP DEL; VAL-256 DEL AND PRO-349, AND CHARACTERIZATION OF VARIANTS HMNDYT1 RP PRO-89. RX PubMed=22341972; DOI=10.1016/j.ajhg.2012.01.018; RA Tuschl K., Clayton P.T., Gospe S.M. Jr., Gulab S., Ibrahim S., Singhi P., RA Aulakh R., Ribeiro R.T., Barsottini O.G., Zaki M.S., Del Rosario M.L., RA Dyack S., Price V., Rideout A., Gordon K., Wevers R.A., Chong W.K., RA Mills P.B.; RT "Syndrome of hepatic cirrhosis, dystonia, polycythemia, and RT hypermanganesemia caused by mutations in SLC30A10, a manganese transporter RT in man."; RL Am. J. Hum. Genet. 90:457-466(2012). RN [7] RP INVOLVEMENT IN HMNDYT1, VARIANT SER-167, INDUCTION BY MANGANESE, AND TISSUE RP SPECIFICITY. RX PubMed=22341971; DOI=10.1016/j.ajhg.2012.01.017; RA Quadri M., Federico A., Zhao T., Breedveld G.J., Battisti C., Delnooz C., RA Severijnen L.A., Di Toro Mammarella L., Mignarri A., Monti L., Sanna A., RA Lu P., Punzo F., Cossu G., Willemsen R., Rasi F., Oostra B.A., RA van de Warrenburg B.P., Bonifati V.; RT "Mutations in SLC30A10 cause parkinsonism and dystonia with RT hypermanganesemia, polycythemia, and chronic liver disease."; RL Am. J. Hum. Genet. 90:467-477(2012). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=22706290; DOI=10.1039/c2mt20088k; RA Bosomworth H.J., Thornton J.K., Coneyworth L.J., Ford D., Valentine R.A.; RT "Efflux function, tissue-specific expression and intracellular trafficking RT of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis."; RL Metallomics 4:771-779(2012). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH RP SLC30A3, AND INDUCTION. RX PubMed=22427991; DOI=10.1371/journal.pone.0033211; RA Patrushev N., Seidel-Rogol B., Salazar G.; RT "Angiotensin II requires zinc and downregulation of the zinc transporters RT ZnT3 and ZnT10 to induce senescence of vascular smooth muscle cells."; RL PLoS ONE 7:E33211-E33211(2012). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF RP THR-196, AND CHARACTERIZATION OF VARIANTS HMNDYT1 PRO-89 AND RP 105-ALA--PRO-107 DEL. RX PubMed=25319704; DOI=10.1523/jneurosci.2329-14.2014; RA Leyva-Illades D., Chen P., Zogzas C.E., Hutchens S., Mercado J.M., RA Swaim C.D., Morrisett R.A., Bowman A.B., Aschner M., Mukhopadhyay S.; RT "SLC30A10 is a cell surface-localized manganese efflux transporter, and RT parkinsonism-causing mutations block its intracellular trafficking and RT efflux activity."; RL J. Neurosci. 34:14079-14095(2014). RN [11] RP INDUCTION. RX PubMed=25582195; DOI=10.1128/mcb.01298-14; RA Ogo O.A., Tyson J., Cockell S.J., Howard A., Valentine R.A., Ford D.; RT "The zinc finger protein ZNF658 regulates the transcription of genes RT involved in zinc homeostasis and affects ribosome biogenesis through the RT zinc transcriptional regulatory element."; RL Mol. Cell. Biol. 35:977-987(2015). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASN-43; CYS-52 AND LEU-242. RX PubMed=27226609; DOI=10.1074/jbc.m116.728014; RA Nishito Y., Tsuji N., Fujishiro H., Takeda T.A., Yamazaki T., Teranishi F., RA Okazaki F., Matsunaga A., Tuschl K., Rao R., Kono S., Miyajima H., RA Narita H., Himeno S., Kambe T.; RT "Direct comparison of manganese detoxification/efflux proteins and RT molecular characterization of ZnT10 protein as a manganese transporter."; RL J. Biol. Chem. 291:14773-14787(2016). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP GLU-25; ASP-40; ASN-43; ASP-47; ASN-127; HIS-244; ASP-248; HIS-333 AND RP HIS-350. RX PubMed=27307044; DOI=10.1074/jbc.m116.726935; RA Zogzas C.E., Aschner M., Mukhopadhyay S.; RT "Structural elements in the transmembrane and cytoplasmic domains of the RT metal transporter SLC30A10 are required for its manganese efflux RT activity."; RL J. Biol. Chem. 291:15940-15957(2016). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, INTERACTION WITH SLC30A2; SLC30A3 RP AND SLC30A4, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-4. RX PubMed=26728129; DOI=10.1111/tra.12371; RA Zhao Y., Feresin R.G., Falcon-Perez J.M., Salazar G.; RT "Differential targeting of SLC30A10/ZnT10 heterodimers to endolysosomal RT compartments modulates EGF-induced MEK/ERK1/2 activity."; RL Traffic 17:267-288(2016). RN [15] RP FUNCTION, TRANSPORTER ACTIVITY, MUTAGENESIS OF ASN-43; ASP-47; HIS-244 AND RP ASP-248, AND SITE. RX PubMed=30755481; DOI=10.1074/jbc.ra118.006816; RA Levy M., Elkoshi N., Barber-Zucker S., Hoch E., Zarivach R., RA Hershfinkel M., Sekler I.; RT "Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn2+ is driven RT by an active Ca2+-coupled exchange."; RL J. Biol. Chem. 294:5879-5889(2019). CC -!- FUNCTION: Calcium:manganese antiporter of the plasma membrane mediating CC the efflux of intracellular manganese coupled to an active CC extracellular calcium exchange (PubMed:30755481). Required for CC intracellular manganese homeostasis, an essential cation for the CC function of several enzymes, including some crucially important for the CC metabolism of neurotransmitters and other neuronal metabolic pathways. CC Manganese can also be cytotoxic and induce oxidative stress, CC mitochondrial dysfunction and apoptosis (PubMed:22341972, CC PubMed:25319704, PubMed:26728129, PubMed:27226609, PubMed:27307044). CC Could also have an intracellular zinc ion transporter activity, CC directly regulating intracellular zinc ion homeostasis and more CC indirectly various signaling pathway and biological processes CC (PubMed:22427991, PubMed:26728129). {ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:25319704, CC ECO:0000269|PubMed:26728129, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Mn(2+)(out) + Ca(2+)(in) = Mn(2+)(in) + Ca(2+)(out); CC Xref=Rhea:RHEA:73059, ChEBI:CHEBI:29035, ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:27226609, CC ECO:0000269|PubMed:27307044, ECO:0000269|PubMed:30755481}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Zn(2+)(in) = Zn(2+)(out); Xref=Rhea:RHEA:29351, CC ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; CC -!- SUBUNIT: Forms homodimers. Forms heterodimers and high-molecular weight CC oligomers with SLC30A3, SLC30A2 and SLC30A4; heterodimerization is CC mediated by covalent-bound tyrosine residues, occurs probably in a CC tissue-specific manner and could mediate the intracellular zinc CC transport activity into early endosomes and recycling endosomes. CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. CC -!- INTERACTION: CC Q6XR72; Q9BRI3: SLC30A2; NbExp=4; IntAct=EBI-13917996, EBI-8644112; CC Q6XR72; Q99726: SLC30A3; NbExp=3; IntAct=EBI-13917996, EBI-10294651; CC Q6XR72; O14863: SLC30A4; NbExp=2; IntAct=EBI-13917996, EBI-13918058; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22706290, CC ECO:0000269|PubMed:25319704, ECO:0000269|PubMed:26728129, CC ECO:0000269|PubMed:27226609, ECO:0000269|PubMed:27307044}; Multi-pass CC membrane protein {ECO:0000255}. Golgi apparatus membrane CC {ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:27226609}; Multi-pass CC membrane protein {ECO:0000255}. Recycling endosome membrane CC {ECO:0000269|PubMed:22427991, ECO:0000269|PubMed:26728129}. Early CC endosome membrane {ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:26728129}; Multi-pass membrane protein CC {ECO:0000255}. Note=Localization to the Golgi and plasma membrane is CC regulated by zinc. {ECO:0000269|PubMed:22706290}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q6XR72-4; Sequence=Displayed; CC Name=2; CC IsoId=Q6XR72-2; Sequence=VSP_029863; CC Name=3; CC IsoId=Q6XR72-3; Sequence=VSP_029864, VSP_029865; CC -!- TISSUE SPECIFICITY: Specifically expressed in fetal liver and fetal CC brain (PubMed:15154973). Expressed in adult tissues with relative CC levels small intestine > liver > testes > brain > ovary > colon > CC cervix > prostate > placenta (PubMed:22706290). Expressed in liver and CC neurons of the nervous system (at protein level) (PubMed:22341971). CC {ECO:0000269|PubMed:15154973, ECO:0000269|PubMed:22341971, CC ECO:0000269|PubMed:22706290}. CC -!- INDUCTION: Down-regulated by zinc (PubMed:22427991, PubMed:22706290, CC PubMed:25582195). Down-regulated by angiotensin-2 (PubMed:22427991). CC Up-regulated by manganese (PubMed:22341971). CC {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22427991, CC ECO:0000269|PubMed:22706290, ECO:0000269|PubMed:25582195}. CC -!- DISEASE: Hypermanganesemia with dystonia 1 (HMNDYT1) [MIM:613280]: A CC metabolic autosomal recessive disorder characterized by dystonia, CC parkinsonism, extrapyramidal signs, severe hypermanganesemia, CC polycythemia, and chronic hepatic disease, including steatosis and CC cirrhosis. {ECO:0000269|PubMed:22341971, ECO:0000269|PubMed:22341972, CC ECO:0000269|PubMed:25319704}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the cation diffusion facilitator (CDF) CC transporter (TC 2.A.4) family. SLC30A subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAP44332.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in position 427.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY212919; AAP44332.1; ALT_SEQ; mRNA. DR EMBL; AL359609; CAB94880.1; -; mRNA. DR EMBL; AC093562; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036078; AAH36078.1; -; mRNA. DR CCDS; CCDS31026.1; -. [Q6XR72-4] DR PIR; T50628; T50628. DR RefSeq; NP_061183.2; NM_018713.2. [Q6XR72-4] DR AlphaFoldDB; Q6XR72; -. DR SMR; Q6XR72; -. DR BioGRID; 120703; 181. DR ComplexPortal; CPX-8462; ZNT10 calcium-coupled manganese antiporter homodimer. DR ComplexPortal; CPX-8463; ZNT2-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8464; ZNT3-ZNT10 proton-coupled zinc antiporter complex. DR ComplexPortal; CPX-8465; ZNT4-ZNT10 proton-coupled zinc antiporter complex. DR FunCoup; Q6XR72; 245. DR IntAct; Q6XR72; 179. DR STRING; 9606.ENSP00000355893; -. DR DrugBank; DB06757; Manganese cation. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR TCDB; 2.A.4.2.5; the cation diffusion facilitator (cdf) family. DR GlyGen; Q6XR72; 1 site. DR iPTMnet; Q6XR72; -. DR PhosphoSitePlus; Q6XR72; -. DR BioMuta; SLC30A10; -. DR DMDM; 311033506; -. DR jPOST; Q6XR72; -. DR MassIVE; Q6XR72; -. DR PaxDb; 9606-ENSP00000355893; -. DR PeptideAtlas; Q6XR72; -. DR ProteomicsDB; 67813; -. [Q6XR72-4] DR ProteomicsDB; 67814; -. [Q6XR72-2] DR ProteomicsDB; 67815; -. [Q6XR72-3] DR Antibodypedia; 3072; 116 antibodies from 18 providers. DR DNASU; 55532; -. DR Ensembl; ENST00000356609.2; ENSP00000349018.2; ENSG00000196660.13. [Q6XR72-3] DR Ensembl; ENST00000366926.4; ENSP00000355893.4; ENSG00000196660.13. [Q6XR72-4] DR GeneID; 55532; -. DR KEGG; hsa:55532; -. DR MANE-Select; ENST00000366926.4; ENSP00000355893.4; NM_018713.3; NP_061183.2. DR UCSC; uc001hlw.4; human. [Q6XR72-4] DR AGR; HGNC:25355; -. DR ClinPGx; PA142670903; -. DR CTD; 55532; -. DR DisGeNET; 55532; -. DR GeneCards; SLC30A10; -. DR GeneReviews; SLC30A10; -. DR HGNC; HGNC:25355; SLC30A10. DR HPA; ENSG00000196660; Group enriched (intestine, liver). DR MalaCards; SLC30A10; -. DR MIM; 611146; gene. DR MIM; 613280; phenotype. DR OpenTargets; ENSG00000196660; -. DR Orphanet; 309854; Cirrhosis-dystonia-polycythemia-hypermanganesemia syndrome. DR VEuPathDB; HostDB:ENSG00000196660; -. DR eggNOG; KOG1483; Eukaryota. DR GeneTree; ENSGT00940000159967; -. DR HOGENOM; CLU_1239780_0_0_1; -. DR InParanoid; Q6XR72; -. DR OMA; FQDCASW; -. DR OrthoDB; 29444at2759; -. DR PAN-GO; Q6XR72; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q6XR72; -. DR PathwayCommons; Q6XR72; -. DR Reactome; R-HSA-425410; Metal ion SLC transporters. DR SignaLink; Q6XR72; -. DR Agora; ENSG00000196660; -. DR BioGRID-ORCS; 55532; 11 hits in 1155 CRISPR screens. DR ChiTaRS; SLC30A10; human. DR GenomeRNAi; 55532; -. DR Pharos; Q6XR72; Tbio. DR PRO; PR:Q6XR72; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q6XR72; protein. DR Bgee; ENSG00000196660; Expressed in jejunal mucosa and 75 other cell types or tissues. DR GO; GO:0005769; C:early endosome; IDA:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IDA:UniProtKB. DR GO; GO:0055038; C:recycling endosome membrane; IDA:UniProtKB. DR GO; GO:0140983; F:calcium:manganese antiporter activity; IDA:UniProtKB. DR GO; GO:0005384; F:manganese ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005385; F:zinc ion transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:1904385; P:cellular response to angiotensin; IDA:UniProtKB. DR GO; GO:0010312; P:detoxification of zinc ion; IBA:GO_Central. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0030026; P:intracellular manganese ion homeostasis; IDA:UniProtKB. DR GO; GO:0006882; P:intracellular zinc ion homeostasis; IDA:UniProtKB. DR GO; GO:0140048; P:manganese ion export across plasma membrane; IDA:UniProtKB. DR GO; GO:0006828; P:manganese ion transport; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0062111; P:zinc ion import into organelle; IDA:UniProtKB. DR GO; GO:0071577; P:zinc ion transmembrane transport; IBA:GO_Central. DR Gene3D; 1.20.1510.10; Cation efflux protein transmembrane domain; 1. DR InterPro; IPR002524; Cation_efflux. DR InterPro; IPR027470; Cation_efflux_CTD. DR InterPro; IPR058533; Cation_efflux_TM. DR InterPro; IPR027469; Cation_efflux_TMD_sf. DR NCBIfam; TIGR01297; CDF; 1. DR PANTHER; PTHR45820:SF3; CALCIUM_MANGANESE ANTIPORTER SLC30A10; 1. DR PANTHER; PTHR45820; FI23527P1; 1. DR Pfam; PF01545; Cation_efflux; 1. DR Pfam; PF16916; ZT_dimer; 1. DR SUPFAM; SSF161111; Cation efflux protein transmembrane domain-like; 1. PE 1: Evidence at protein level; KW Alternative splicing; Antiport; Cell membrane; Disease variant; Dystonia; KW Endosome; Golgi apparatus; Ion transport; Manganese; Membrane; KW Neurodegeneration; Parkinsonism; Proteomics identification; KW Reference proteome; Transmembrane; Transmembrane helix; Transport; Zinc; KW Zinc transport. FT CHAIN 1..485 FT /note="Calcium/manganese antiporter SLC30A10" FT /id="PRO_0000312580" FT TOPO_DOM 1..10 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 11..31 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 32..40 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 41..61 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 62..81 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 82..102 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 103..113 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 114..134 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 135..244 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 245..265 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 266..278 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 279..299 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 300..485 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 167..196 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 308..485 FT /note="Required for plasma membrane localization" FT /evidence="ECO:0000269|PubMed:25319704" FT SITE 43 FT /note="Important for coupling of manganese to calcium FT transport" FT /evidence="ECO:0000269|PubMed:30755481" FT VAR_SEQ 1..245 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_029863" FT VAR_SEQ 214..223 FT /note="GDSFNTQNEP -> ELIHNTRFLL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029864" FT VAR_SEQ 224..485 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_029865" FT VARIANT 89 FT /note="L -> P (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; loss of function in FT intracellular manganese ion homeostasis; FT dbSNP:rs281860284)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072573" FT VARIANT 105..107 FT /note="Missing (in HMNDYT1; loss of localization to the FT plasma membrane; retained in the endoplasmic reticulum; FT increased proteasomal degradation; decreased function in FT intracellular manganese ion homeostasis)" FT /evidence="ECO:0000269|PubMed:22341972, FT ECO:0000269|PubMed:25319704" FT /id="VAR_072574" FT VARIANT 167 FT /note="F -> S (in dbSNP:rs281860286)" FT /evidence="ECO:0000269|PubMed:22341971" FT /id="VAR_072575" FT VARIANT 256 FT /note="Missing (in HMNDYT1)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072576" FT VARIANT 349 FT /note="L -> P (in HMNDYT1; dbSNP:rs281860291)" FT /evidence="ECO:0000269|PubMed:22341972" FT /id="VAR_072577" FT MUTAGEN 4 FT /note="Y->F: Decreased interaction with SLC30A3. No effect FT on self-association. Decreased zinc ion transmembrane FT transporter activity. Decreased EGF-induced ERK1/2 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:26728129" FT MUTAGEN 25 FT /note="E->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 40 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 43 FT /note="N->A: No effect on localization to the plasma FT membrane. Changed calcium:manganese antiporter activity. FT Enhanced coupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:27307044, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->H: No effect on localization to the plasma FT membrane. Loss of calcium:manganese antiporter activity. FT Loss of calcium:manganese antiporter activity and increased FT zinc ion transmembrane transporter activity; when FT associated with V-52 and F-242." FT /evidence="ECO:0000269|PubMed:27226609, FT ECO:0000269|PubMed:30755481" FT MUTAGEN 43 FT /note="N->T: Loss of calcium:manganese antiporter activity. FT Uncoupling between manganese and calcium exchange." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 47 FT /note="D->A: No effect on localization to the plasma FT membrane. No effect on calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 47 FT /note="D->E: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 52 FT /note="C->V: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and F-242." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 127 FT /note="N->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-244." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 196 FT /note="T->P: Loss of localization to the plasma membrane." FT /evidence="ECO:0000269|PubMed:25319704" FT MUTAGEN 242 FT /note="L->F: Loss of calcium:manganese antiporter activity FT and increased zinc ion transmembrane transporter activity; FT when associated with H-43 and V-52." FT /evidence="ECO:0000269|PubMed:27226609" FT MUTAGEN 244 FT /note="H->A: No effect on localization to the plasma FT membrane. No effect on localization to the plasma membrane FT and decreased calcium:manganese antiporter activity; when FT associated with A-127." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 244 FT /note="H->D: Loss of calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:30755481" FT MUTAGEN 248 FT /note="D->A: No effect on localization to the plasma FT membrane. Loss of manganese ion export across plasma FT membrane." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 333 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" FT MUTAGEN 350 FT /note="H->A: Decreased calcium:manganese antiporter FT activity." FT /evidence="ECO:0000269|PubMed:27307044" SQ SEQUENCE 485 AA; 52684 MW; 96A3495EF026DE94 CRC64; MGRYSGKTCR LLFMLVLTVA FFVAELVSGY LGNSIALLSD SFNMLSDLIS LCVGLSAGYI ARRPTRGFSA TYGYARAEVV GALSNAVFLT ALCFTIFVEA VLRLARPERI DDPELVLIVG VLGLLVNVVG LLIFQDCAAW FACCLRGRSR RLQQRQQLAE GCVPGAFGGP QGAEDPRRAA DPTAPGSDSA VTLRGTSVER KREKGATVFA NVAGDSFNTQ NEPEDMMKKE KKSEALNIRG VLLHVMGDAL GSVVVVITAI IFYVLPLKSE DPCNWQCYID PSLTVLMVII ILSSAFPLIK ETAAILLQMV PKGVNMEELM SKLSAVPGIS SVHEVHIWEL VSGKIIATLH IKYPKDRGYQ DASTKIREIF HHAGIHNVTI QFENVDLKEP LEQKDLLLLC NSPCISKGCA KQLCCPPGAL PLAHVNGCAE HNGGPSLDTY GSDGLSRRDA REVAIEVSLD SCLSDHGQSL NKTQEDQCYV NRTHF //