RBCC Red Blood Cell Collection

HERC2 [Confidence: low (only semi-automatic identification from reviews)]
E3 ubiquitin-protein ligase HERC2; 6.3.2.- (HECT domain and RCC1-like domain-containing protein 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt O95714
ID HERC2_HUMAN Reviewed; 4834 AA.
AC O95714; Q86SV7; Q86SV8; Q86SV9; Q86YY3; Q86YY4; Q86YY5; Q86YY6;
read moreAC Q86YY7; Q86YY8; Q86YY9; Q86YZ0; Q86YZ1;
DT 04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 2.
DT 22-JAN-2014, entry version 116.
DE RecName: Full=E3 ubiquitin-protein ligase HERC2;
DE EC=6.3.2.-;
DE AltName: Full=HECT domain and RCC1-like domain-containing protein 2;
GN Name=HERC2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9949213; DOI=10.1093/hmg/8.3.533;
RA Ji Y., Walkowicz M.J., Buiting K., Johnson D.K., Tarvin R.E.,
RA Rinchik E.M., Horsthemke B., Stubbs L., Nicholls R.D.;
RT "The ancestral gene for transcribed, low-copy repeats in the Prader-
RT Willi/Angelman region encodes a large protein implicated in protein
RT trafficking, which is deficient in mice with neuromuscular and
RT spermiogenic abnormalities.";
RL Hum. Mol. Genet. 8:533-542(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 2818-2895; 2909-2957; 2963-3290;
RP 3317-3363; 3389-3430; 3458-3495; 3512-3527; 3533-3633; 3635-3821;
RP 3826-4084; 4097-4505 AND 4529-4834, AND GENE STRUCTURE.
RX PubMed=10720573; DOI=10.1101/gr.10.3.319;
RA Ji Y., Rebert N.A., Joslin J.M., Higgins M.J., Schultz R.A.,
RA Nicholls R.D.;
RT "Structure of the highly conserved HERC2 gene and of multiple
RT partially duplicated paralogs in human.";
RL Genome Res. 10:319-329(2000).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2454 AND SER-2928, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [5]
RP INVOLVEMENT IN SHEP1.
RX PubMed=18252221; DOI=10.1016/j.ajhg.2007.10.003;
RA Kayser M., Liu F., Janssens A.C.J.W., Rivadeneira F., Lao O.,
RA van Duijn K., Vermeulen M., Arp P., Jhamai M.M., van Ijcken W.F.J.,
RA den Dunnen J.T., Heath S., Zelenika D., Despriet D.D.G.,
RA Klaver C.C.W., Vingerling J.R., de Jong P.T.V.M., Hofman A.,
RA Aulchenko Y.S., Uitterlinden A.G., Oostra B.A., van Duijn C.M.;
RT "Three genome-wide association studies and a linkage analysis identify
RT HERC2 as a human iris color gene.";
RL Am. J. Hum. Genet. 82:411-423(2008).
RN [6]
RP INVOLVEMENT IN SHEP1.
RX PubMed=18252222; DOI=10.1016/j.ajhg.2007.11.005;
RA Sturm R.A., Duffy D.L., Zhao Z.Z., Leite F.P.M., Stark M.S.,
RA Hayward N.K., Martin N.G., Montgomery G.W.;
RT "A single SNP in an evolutionary conserved region within intron 86 of
RT the HERC2 gene determines human blue-brown eye color.";
RL Am. J. Hum. Genet. 82:424-431(2008).
RN [7]
RP INVOLVEMENT IN SHEP1, AND REGULATION OF OCA2.
RX PubMed=18172690; DOI=10.1007/s00439-007-0460-x;
RA Eiberg H., Troelsen J., Nielsen M., Mikkelsen A., Mengel-From J.,
RA Kjaer K.W., Hansen L.;
RT "Blue eye color in humans may be caused by a perfectly associated
RT founder mutation in a regulatory element located within the HERC2 gene
RT inhibiting OCA2 expression.";
RL Hum. Genet. 123:177-187(2008).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2928; SER-4810; SER-4811
RP AND SER-4814, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2454, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [11]
RP MISCELLANEOUS.
RX PubMed=20457063; DOI=10.1016/j.fsigen.2009.12.004;
RA Mengel-From J., Borsting C., Sanchez J.J., Eiberg H., Morling N.;
RT "Human eye colour and HERC2, OCA2 and MATP.";
RL Forensic Sci. Int. Genet. 4:323-328(2010).
RN [12]
RP FUNCTION, INTERACTION WITH RNF8, PHOSPHORYLATION AT THR-4827,
RP MUTAGENESIS OF THR-4827, AND SUBCELLULAR LOCATION.
RX PubMed=20023648; DOI=10.1038/ncb2008;
RA Bekker-Jensen S., Rendtlew Danielsen J., Fugger K., Gromova I.,
RA Nerstedt A., Lukas C., Bartek J., Lukas J., Mailand N.;
RT "HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors
RT on damaged chromosomes.";
RL Nat. Cell Biol. 12:80-86(2010).
RN [13]
RP FUNCTION, UBIQUITIN LIGASE ACTIVITY, INTERACTION WITH XPA, AND
RP SUBCELLULAR LOCATION.
RX PubMed=20304803; DOI=10.1073/pnas.0915085107;
RA Kang T.H., Lindsey-Boltz L.A., Reardon J.T., Sancar A.;
RT "Circadian control of XPA and excision repair of cisplatin-DNA damage
RT by cryptochrome and HERC2 ubiquitin ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:4890-4895(2010).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2454 AND SER-2928, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-647; THR-1944 AND
RP SER-2928, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [17]
RP SUMOYLATION, FUNCTION, SUMO-BINDING, DOMAIN, INTERACTION WITH RNF8,
RP AND MUTAGENESIS OF CYS-2708 AND CYS-2711.
RX PubMed=22508508; DOI=10.1083/jcb.201106152;
RA Danielsen J.R., Povlsen L.K., Villumsen B.H., Streicher W.,
RA Nilsson J., Wikstrom M., Bekker-Jensen S., Mailand N.;
RT "DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a
RT novel SUMO-binding Zinc finger.";
RL J. Cell Biol. 197:179-187(2012).
RN [18]
RP INTERACTION WITH CCP110; CEP97 AND NEURL4, AND SUBCELLULAR LOCATION.
RX PubMed=22261722; DOI=10.1074/mcp.M111.014233;
RA Al-Hakim A.K., Bashkurov M., Gingras A.C., Durocher D., Pelletier L.;
RT "Interaction proteomics identify NEURL4 and the HECT E3 ligase HERC2
RT as novel modulators of centrosome architecture.";
RL Mol. Cell. Proteomics 11:M111.014233.01-M111.014233.14(2012).
RN [19]
RP VARIANT LEU-594, CHARACTERIZATIO OF VARIANT LEU-594, AND POSSIBLE
RP ASSOCIATION WITH ASD.
RX PubMed=23065719; DOI=10.1002/humu.22237;
RA Puffenberger E.G., Jinks R.N., Wang H., Xin B., Fiorentini C.,
RA Sherman E.A., Degrazio D., Shaw C., Sougnez C., Cibulskis K.,
RA Gabriel S., Kelley R.I., Morton D.H., Strauss K.A.;
RT "A homozygous missense mutation in HERC2 associated with global
RT developmental delay and autism spectrum disorder.";
RL Hum. Mutat. 33:1639-1646(2012).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that regulates ubiquitin-
CC dependent retention of repair proteins on damaged chromosomes.
CC Recruited to sites of DNA damage in response to ionizing radiation
CC (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA
CC damage-induced formation of 'Lys-63'-linked ubiquitin chains. Acts
CC as a mediator of binding specificity between UBE2N and RNF8.
CC Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein
CC ligase that promotes the ubiquitination and proteasomal
CC degradation of XPA which influences the circadian oscillation of
CC DNA excision repair activity.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts (when phosphorylated at Thr-4827 and
CC sumoylated) with RNF8 (via FHA domain); this interaction increases
CC after ionizing radiation (IR) treatment. Interacts with XPA.
CC Interacts with NEURL4. Via its interaction with NEURL4, may
CC indirectly interact with CCP110 and CEP97.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton,
CC microtubule organizing center, centrosome, centriole. Nucleus.
CC Note=Recruited to sites of DNA damage in response to ionizing
CC radiation (IR) via its interaction with RNF8. May loose
CC association with centrosomes during mitosis.
CC -!- DOMAIN: The ZZ-type zinc finger mediates binding to SUMO1, and at
CC lowe level SUMO2.
CC -!- PTM: Phosphorylation at Thr-4827 is required for interaction with
CC RNF8.
CC -!- PTM: Sumoylated with SUMO1 by PIAS4 in response to double-strand
CC breaks (DSBs), promoting the interaction with RNF8.
CC -!- POLYMORPHISM: Genetic variants in HERC2 define the skin/hair/eye
CC pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as
CC skin/hair/eye pigmentation type 1, blue/nonblue eyes or
CC skin/hair/eye pigmentation type 1, blue/brown eyes or
CC skin/hair/eye pigmentation type 1, blond/brown hair or eye color,
CC brown/blue or eye color, blue/nonblue or eye color type 3 (EYCL3)
CC or brown eye color type 2 (BEY2) or hair color type 3 (HCL3).
CC Hair, eye and skin pigmentation are among the most visible
CC examples of human phenotypic variation, with a broad normal range
CC that is subject to substantial geographic stratification. In the
CC case of skin, individuals tend to have lighter pigmentation with
CC increasing distance from the equator. By contrast, the majority of
CC variation in human eye and hair color is found among individuals
CC of European ancestry, with most other human populations fixed for
CC brown eyes and black hair.
CC -!- DISEASE: Note=Defects in HERC2 may be responsible for an autism
CC spectrum disorder (ASD), characterized by cognitive delay,
CC autistic behavior and gait instability.
CC -!- MISCELLANEOUS: A regulatory element withinin an intron of the
CC HERC2 gene inhibits OCA2 promoter. There are several single
CC nucleotide polymorphisms within the OCA2 gene and within the HERC2
CC gene that have a statistical association with human eye color.
CC -!- SIMILARITY: Contains 1 cytochrome b5 heme-binding domain.
CC -!- SIMILARITY: Contains 1 DOC domain.
CC -!- SIMILARITY: Contains 1 HECT (E6AP-type E3 ubiquitin-protein
CC ligase) domain.
CC -!- SIMILARITY: Contains 1 MIB/HERC2 domain.
CC -!- SIMILARITY: Contains 19 RCC1 repeats.
CC -!- SIMILARITY: Contains 6 WD repeats.
CC -!- SIMILARITY: Contains 1 ZZ-type zinc finger.
CC -!- WEB RESOURCE: Name=Hect domain and RLD 2 (HERC2); Note=Leiden Open
CC Variation Database (LOVD);
CC URL="http://www.LOVD.nl/HERC2";
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DR EMBL; AF071172; AAD08657.1; -; mRNA.
DR EMBL; AC091304; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC126332; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135329; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF224243; AAO27473.1; -; Genomic_DNA.
DR EMBL; AF224242; AAO27473.1; JOINED; Genomic_DNA.
DR EMBL; AF224245; AAO27474.1; -; Genomic_DNA.
DR EMBL; AF224244; AAO27474.1; JOINED; Genomic_DNA.
DR EMBL; AF224249; AAO27475.1; -; Genomic_DNA.
DR EMBL; AF224246; AAO27475.1; JOINED; Genomic_DNA.
DR EMBL; AF224247; AAO27475.1; JOINED; Genomic_DNA.
DR EMBL; AF224248; AAO27475.1; JOINED; Genomic_DNA.
DR EMBL; AF224251; AAO27476.1; -; Genomic_DNA.
DR EMBL; AF224250; AAO27476.1; JOINED; Genomic_DNA.
DR EMBL; AF224255; AAO27479.1; -; Genomic_DNA.
DR EMBL; AF224254; AAO27479.1; JOINED; Genomic_DNA.
DR EMBL; AF224252; AAO27477.1; -; Genomic_DNA.
DR EMBL; AF224253; AAO27478.1; -; Genomic_DNA.
DR EMBL; AF224257; AAO27480.1; -; Genomic_DNA.
DR EMBL; AF224256; AAO27480.1; JOINED; Genomic_DNA.
DR EMBL; AF225401; AAO27481.1; -; Genomic_DNA.
DR EMBL; AF225400; AAO27481.1; JOINED; Genomic_DNA.
DR EMBL; AF225404; AAO27482.1; -; Genomic_DNA.
DR EMBL; AF225402; AAO27482.1; JOINED; Genomic_DNA.
DR EMBL; AF225403; AAO27482.1; JOINED; Genomic_DNA.
DR EMBL; AF225407; AAO27483.1; -; Genomic_DNA.
DR EMBL; AF225405; AAO27483.1; JOINED; Genomic_DNA.
DR EMBL; AF225406; AAO27483.1; JOINED; Genomic_DNA.
DR EMBL; AF225409; AAO27484.1; -; Genomic_DNA.
DR EMBL; AF225408; AAO27484.1; JOINED; Genomic_DNA.
DR RefSeq; NP_004658.3; NM_004667.5.
DR UniGene; Hs.434890; -.
DR UniGene; Hs.610412; -.
DR UniGene; Hs.741019; -.
DR PDB; 2KEO; NMR; -; A=1203-1296.
DR PDB; 3KCI; X-ray; 1.80 A; A=3950-4321.
DR PDB; 4L1M; X-ray; 2.60 A; A/B/C=417-790.
DR PDBsum; 2KEO; -.
DR PDBsum; 3KCI; -.
DR PDBsum; 4L1M; -.
DR ProteinModelPortal; O95714; -.
DR SMR; O95714; 1205-1296, 1867-1929, 3953-4318.
DR DIP; DIP-37632N; -.
DR IntAct; O95714; 14.
DR MINT; MINT-8415335; -.
DR PhosphoSite; O95714; -.
DR PaxDb; O95714; -.
DR PRIDE; O95714; -.
DR Ensembl; ENST00000261609; ENSP00000261609; ENSG00000128731.
DR Ensembl; ENST00000576092; ENSP00000458767; ENSG00000263162.
DR GeneID; 8924; -.
DR KEGG; hsa:8924; -.
DR UCSC; uc001zbj.4; human.
DR CTD; 8924; -.
DR GeneCards; GC15M028356; -.
DR H-InvDB; HIX0012044; -.
DR H-InvDB; HIX0017540; -.
DR H-InvDB; HIX0038121; -.
DR H-InvDB; HIX0038320; -.
DR H-InvDB; HIX0038830; -.
DR H-InvDB; HIX0173226; -.
DR H-InvDB; HIX0173299; -.
DR H-InvDB; HIX0194348; -.
DR HGNC; HGNC:4868; HERC2.
DR HPA; CAB017188; -.
DR MIM; 227220; phenotype.
DR MIM; 605837; gene.
DR neXtProt; NX_O95714; -.
DR Orphanet; 329195; Developmental delay with autism spectrum disorder and gait instability.
DR PharmGKB; PA29243; -.
DR eggNOG; COG5021; -.
DR HOVERGEN; HBG081598; -.
DR InParanoid; O95714; -.
DR KO; K10595; -.
DR OMA; GHGTDVH; -.
DR PhylomeDB; O95714; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; O95714; -.
DR GeneWiki; HERC2; -.
DR GenomeRNAi; 8924; -.
DR NextBio; 33552; -.
DR PRO; PR:O95714; -.
DR ArrayExpress; O95714; -.
DR Bgee; O95714; -.
DR Genevestigator; O95714; -.
DR GO; GO:0005814; C:centriole; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; NAS:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0032183; F:SUMO binding; IDA:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006281; P:DNA repair; IDA:UniProtKB.
DR GO; GO:0006886; P:intracellular protein transport; NAS:UniProtKB.
DR GO; GO:0042787; P:protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:RefGenome.
DR Gene3D; 2.130.10.30; -; 3.
DR Gene3D; 2.30.30.30; -; 1.
DR Gene3D; 2.60.120.260; -; 1.
DR Gene3D; 3.10.120.10; -; 1.
DR InterPro; IPR004939; APC_su10/DOC_dom.
DR InterPro; IPR006624; Beta-propeller_rpt_TECPR.
DR InterPro; IPR021097; CPH_domain.
DR InterPro; IPR001199; Cyt_B5-like_heme/steroid-bd.
DR InterPro; IPR008979; Galactose-bd-like.
DR InterPro; IPR000569; HECT.
DR InterPro; IPR010606; Mib_Herc2.
DR InterPro; IPR009091; RCC1/BLIP-II.
DR InterPro; IPR000408; Reg_chr_condens.
DR InterPro; IPR014722; Rib_L2_dom2.
DR InterPro; IPR000433; Znf_ZZ.
DR Pfam; PF03256; APC10; 1.
DR Pfam; PF11515; Cul7; 1.
DR Pfam; PF00173; Cyt-b5; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF06701; MIB_HERC2; 1.
DR Pfam; PF00415; RCC1; 18.
DR Pfam; PF00569; ZZ; 1.
DR PRINTS; PR00633; RCCNDNSATION.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00706; TECPR; 5.
DR SMART; SM00291; ZnF_ZZ; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF50985; SSF50985; 3.
DR SUPFAM; SSF55856; SSF55856; 1.
DR SUPFAM; SSF56204; SSF56204; 1.
DR PROSITE; PS00191; CYTOCHROME_B5_1; FALSE_NEG.
DR PROSITE; PS50255; CYTOCHROME_B5_2; 1.
DR PROSITE; PS51284; DOC; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS51416; MIB_HERC2; 1.
DR PROSITE; PS00625; RCC1_1; FALSE_NEG.
DR PROSITE; PS00626; RCC1_2; 1.
DR PROSITE; PS50012; RCC1_3; 18.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; FALSE_NEG.
DR PROSITE; PS50294; WD_REPEATS_REGION; FALSE_NEG.
DR PROSITE; PS01357; ZF_ZZ_1; 1.
DR PROSITE; PS50135; ZF_ZZ_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Coiled coil; Complete proteome; Cytoplasm; Cytoskeleton;
KW Disease mutation; DNA damage; DNA repair; Ligase; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; Ubl conjugation;
KW Ubl conjugation pathway; WD repeat; Zinc; Zinc-finger.
FT CHAIN 1 4834 E3 ubiquitin-protein ligase HERC2.
FT /FTId=PRO_0000229739.
FT REPEAT 2 46 WD 1.
FT REPEAT 286 327 WD 2.
FT REPEAT 490 529 WD 3.
FT REPEAT 513 568 RCC1 1.
FT REPEAT 569 620 RCC1 2.
FT REPEAT 623 674 RCC1 3.
FT REPEAT 675 726 RCC1 4.
FT REPEAT 704 743 WD 4.
FT REPEAT 728 778 RCC1 5.
FT DOMAIN 1207 1283 Cytochrome b5 heme-binding.
FT DOMAIN 1859 1932 MIB/HERC2.
FT DOMAIN 2759 2936 DOC.
FT REPEAT 2958 3009 RCC1 6.
FT REPEAT 3010 3064 RCC1 7.
FT REPEAT 3065 3116 RCC1 8.
FT REPEAT 3118 3168 RCC1 9.
FT REPEAT 3171 3222 RCC1 10.
FT REPEAT 3224 3274 RCC1 11.
FT REPEAT 3275 3326 RCC1 12.
FT REPEAT 3926 3967 WD 5.
FT REPEAT 3951 4002 RCC1 13.
FT REPEAT 4004 4056 RCC1 14.
FT REPEAT 4058 4108 RCC1 15.
FT REPEAT 4110 4162 RCC1 16.
FT REPEAT 4164 4214 RCC1 17.
FT REPEAT 4216 4266 RCC1 18.
FT REPEAT 4241 4283 WD 6.
FT REPEAT 4268 4318 RCC1 19.
FT DOMAIN 4457 4794 HECT.
FT ZN_FING 2702 2749 ZZ-type.
FT COILED 948 980 Potential.
FT ACT_SITE 4762 4762 Glycyl thioester intermediate (By
FT similarity).
FT MOD_RES 647 647 Phosphothreonine.
FT MOD_RES 1577 1577 Phosphoserine (By similarity).
FT MOD_RES 1944 1944 Phosphothreonine.
FT MOD_RES 2454 2454 Phosphoserine.
FT MOD_RES 2928 2928 Phosphoserine.
FT MOD_RES 4810 4810 Phosphoserine.
FT MOD_RES 4811 4811 Phosphoserine.
FT MOD_RES 4814 4814 Phosphoserine.
FT MOD_RES 4827 4827 Phosphothreonine.
FT VARIANT 594 594 P -> L (probable disease-associated
FT mutation found in patients with cognitive
FT delay, autistic behavior and gait
FT instability; results in abnormal protein
FT aggregation).
FT /FTId=VAR_069282.
FT MUTAGEN 2708 2708 C->S: Abolishes binding to SUMO; when
FT associated with S-2711.
FT MUTAGEN 2711 2711 C->S: Abolishes binding to SUMO; when
FT associated with S-2708.
FT MUTAGEN 4827 4827 T->A: Prevents HERC2 C-terminal fragment
FT binding to endogenous RNF8.
FT CONFLICT 1053 1053 L -> W (in Ref. 1; AAD08657).
FT CONFLICT 1150 1150 G -> D (in Ref. 1; AAD08657).
FT CONFLICT 1354 1354 S -> R (in Ref. 1; AAD08657).
FT CONFLICT 1566 1566 T -> M (in Ref. 1; AAD08657).
FT CONFLICT 1753 1753 K -> T (in Ref. 1; AAD08657).
FT CONFLICT 2444 2444 R -> H (in Ref. 1; AAD08657).
FT CONFLICT 2881 2881 C -> Y (in Ref. 1; AAD08657).
FT CONFLICT 3070 3070 S -> W (in Ref. 3; AAO27475).
FT CONFLICT 3346 3346 P -> R (in Ref. 3; AAO27476).
FT CONFLICT 3583 3584 VA -> MP (in Ref. 3; AAO27480).
FT CONFLICT 3597 3597 D -> N (in Ref. 3; AAO27480).
FT CONFLICT 3808 3808 F -> S (in Ref. 3; AAO27481).
FT STRAND 425 430
FT HELIX 446 449
FT STRAND 453 458
FT STRAND 460 467
FT STRAND 472 476
FT STRAND 495 499
FT STRAND 505 511
FT STRAND 516 520
FT HELIX 523 525
FT STRAND 528 531
FT STRAND 535 540
FT HELIX 542 544
FT HELIX 549 551
FT STRAND 552 558
FT STRAND 560 567
FT STRAND 572 576
FT HELIX 579 581
FT STRAND 585 587
FT STRAND 591 596
FT HELIX 598 600
FT STRAND 605 610
FT STRAND 616 621
FT STRAND 626 630
FT HELIX 633 635
FT STRAND 638 642
FT STRAND 645 650
FT HELIX 652 654
FT STRAND 659 665
FT STRAND 668 673
FT STRAND 678 682
FT HELIX 685 687
FT STRAND 691 693
FT STRAND 697 702
FT HELIX 704 706
FT STRAND 711 716
FT STRAND 718 725
FT STRAND 730 735
FT STRAND 746 754
FT STRAND 763 768
FT STRAND 770 777
FT TURN 781 783
FT HELIX 1212 1221
FT STRAND 1225 1228
FT STRAND 1231 1234
FT HELIX 1235 1242
FT HELIX 1250 1252
FT HELIX 1257 1266
FT HELIX 1270 1273
FT HELIX 1274 1277
FT STRAND 1278 1282
FT HELIX 1285 1288
FT STRAND 3954 3959
FT STRAND 3971 3978
FT HELIX 3980 3984
FT STRAND 3987 3993
FT STRAND 3996 4001
FT STRAND 4006 4010
FT HELIX 4013 4015
FT STRAND 4018 4022
FT STRAND 4025 4030
FT HELIX 4032 4034
FT STRAND 4039 4043
FT STRAND 4049 4055
FT STRAND 4060 4064
FT HELIX 4067 4069
FT STRAND 4073 4075
FT STRAND 4079 4084
FT HELIX 4086 4088
FT STRAND 4093 4098
FT STRAND 4100 4107
FT STRAND 4112 4116
FT HELIX 4119 4121
FT STRAND 4125 4127
FT STRAND 4131 4136
FT HELIX 4138 4140
FT STRAND 4145 4150
FT STRAND 4156 4161
FT TURN 4162 4164
FT STRAND 4165 4170
FT HELIX 4173 4175
FT STRAND 4178 4181
FT STRAND 4185 4190
FT HELIX 4192 4194
FT STRAND 4199 4205
FT STRAND 4208 4213
FT STRAND 4218 4222
FT HELIX 4225 4227
FT STRAND 4231 4233
FT STRAND 4237 4242
FT HELIX 4244 4246
FT STRAND 4251 4256
FT STRAND 4258 4265
FT STRAND 4270 4274
FT STRAND 4283 4285
FT STRAND 4289 4294
FT HELIX 4296 4298
FT STRAND 4305 4309
FT STRAND 4312 4316
SQ SEQUENCE 4834 AA; 527228 MW; A323DC1DA6B221D0 CRC64;
MPSESFCLAA QARLDSKWLK TDIQLAFTRD GLCGLWNEMV KDGEIVYTGT ESTQNGELPP
RKDDSVEPSG TKKEDLNDKE KKDEEETPAP IYRAKSILDS WVWGKQPDVN ELKECLSVLV
KEQQALAVQS ATTTLSALRL KQRLVILERY FIALNRTVFQ ENVKVKWKSS GISLPPVDKK
SSRPAGKGVE GLARVGSRAA LSFAFAFLRR AWRSGEDADL CSELLQESLD ALRALPEASL
FDESTVSSVW LEVVERATRF LRSVVTGDVH GTPATKGPGS IPLQDQHLAL AILLELAVQR
GTLSQMLSAI LLLLQLWDSG AQETDNERSA QGTSAPLLPL LQRFQSIICR KDAPHSEGDM
HLLSGPLSPN ESFLRYLTLP QDNELAIDLR QTAVVVMAHL DRLATPCMPP LCSSPTSHKG
SLQEVIGWGL IGWKYYANVI GPIQCEGLAN LGVTQIACAE KRFLILSRNG RVYTQAYNSD
TLAPQLVQGL ASRNIVKIAA HSDGHHYLAL AATGEVYSWG CGDGGRLGHG DTVPLEEPKV
ISAFSGKQAG KHVVHIACGS TYSAAITAEG ELYTWGRGNY GRLGHGSSED EAIPMLVAGL
KGLKVIDVAC GSGDAQTLAV TENGQVWSWG DGDYGKLGRG GSDGCKTPKL IEKLQDLDVV
KVRCGSQFSI ALTKDGQVYS WGKGDNQRLG HGTEEHVRYP KLLEGLQGKK VIDVAAGSTH
CLALTEDSEV HSWGSNDQCQ HFDTLRVTKP EPAALPGLDT KHIVGIACGP AQSFAWSSCS
EWSIGLRVPF VVDICSMTFE QLDLLLRQVS EGMDGSADWP PPQEKECVAV ATLNLLRLQL
HAAISHQVDP EFLGLGLGSI LLNSLKQTVV TLASSAGVLS TVQSAAQAVL QSGWSVLLPT
AEERARALSA LLPCAVSGNE VNISPGRRFM IDLLVGSLMA DGGLESALHA AITAEIQDIE
AKKEAQKEKE IDEQEANAST FHRSRTPLDK DLINTGICES SGKQCLPLVQ LIQQLLRNIA
SQTVARLKDV ARRISSCLDF EQHSRERSAS LDLLLRFQRL LISKLYPGES IGQTSDISSP
ELMGVGSLLK KYTALLCTHI GDILPVAASI ASTSWRHFAE VAYIVEGDFT GVLLPELVVS
IVLLLSKNAG LMQEAGAVPL LGGLLEHLDR FNHLAPGKER DDHEELAWPG IMESFFTGQN
CRNNEEVTLI RKADLENHNK DGGFWTVIDG KVYDIKDFQT QSLTGNSILA QFAGEDPVVA
LEAALQFEDT RESMHAFCVG QYLEPDQEIV TIPDLGSLSS PLIDTERNLG LLLGLHASYL
AMSTPLSPVE IECAKWLQSS IFSGGLQTSQ IHYSYNEEKD EDHCSSPGGT PASKSRLCSH
RRALGDHSQA FLQAIADNNI QDHNVKDFLC QIERYCRQCH LTTPIMFPPE HPVEEVGRLL
LCCLLKHEDL GHVALSLVHA GALGIEQVKH RTLPKSVVDV CRVVYQAKCS LIKTHQEQGR
SYKEVCAPVI ERLRFLFNEL RPAVCNDLSI MSKFKLLSSL PRWRRIAQKI IRERRKKRVP
KKPESTDDEE KIGNEESDLE EACILPHSPI NVDKRPIAIK SPKDKWQPLL STVTGVHKYK
WLKQNVQGLY PQSPLLSTIA EFALKEEPVD VEKMRKCLLK QLERAEVRLE GIDTILKLAS
KNFLLPSVQY AMFCGWQRLI PEGIDIGEPL TDCLKDVDLI PPFNRMLLEV TFGKLYAWAV
QNIRNVLMDA SAKFKELGIQ PVPLQTITNE NPSGPSLGTI PQARFLLVML SMLTLQHGAN
NLDLLLNSGM LALTQTALRL IGPSCDNVEE DMNASAQGAS ATVLEETRKE TAPVQLPVSG
PELAAMMKIG TRVMRGVDWK WGDQDGPPPG LGRVIGELGE DGWIRVQWDT GSTNSYRMGK
EGKYDLKLAE LPAAAQPSAE DSDTEDDSEA EQTERNIHPT AMMFTSTINL LQTLCLSAGV
HAEIMQSEAT KTLCGLLRML VESGTTDKTS SPNRLVYREQ HRSWCTLGFV RSIALTPQVC
GALSSPQWIT LLMKVVEGHA PFTATSLQRQ ILAVHLLQAV LPSWDKTERA RDMKCLVEKL
FDFLGSLLTT CSSDVPLLRE STLRRRRVRP QASLTATHSS TLAEEVVALL RTLHSLTQWN
GLINKYINSQ LRSITHSFVG RPSEGAQLED YFPDSENPEV GGLMAVLAVI GGIDGRLRLG
GQVMHDEFGE GTVTRITPKG KITVQFSDMR TCRVCPLNQL KPLPAVAFNV NNLPFTEPML
SVWAQLVNLA GSKLEKHKIK KSTKQAFAGQ VDLDLLRCQQ LKLYILKAGR ALLSHQDKLR
QILSQPAVQE TGTVHTDDGA VVSPDLGDMS PEGPQPPMIL LQQLLASATQ PSPVKAIFDK
QELEAAALAV CQCLAVESTH PSSPGFEDCS SSEATTPVAV QHIRPARVKR RKQSPVPALP
IVVQLMEMGF SRRNIEFALK SLTGASGNAS SLPGVEALVG WLLDHSDIQV TELSDADTVS
DEYSDEEVVE DVDDAAYSMS TGAVVTESQT YKKRADFLSN DDYAVYVREN IQVGMMVRCC
RAYEEVCEGD VGKVIKLDRD GLHDLNVQCD WQQKGGTYWV RYIHVELIGY PPPSSSSHIK
IGDKVRVKAS VTTPKYKWGS VTHQSVGVVK AFSANGKDII VDFPQQSHWT GLLSEMELVP
SIHPGVTCDG CQMFPINGSR FKCRNCDDFD FCETCFKTKK HNTRHTFGRI NEPGQSAVFC
GRSGKQLKRC HSSQPGMLLD SWSRMVKSLN VSSSVNQASR LIDGSEPCWQ SSGSQGKHWI
RLEIFPDVLV HRLKMIVDPA DSSYMPSLVV VSGGNSLNNL IELKTININP SDTTVPLLND
CTEYHRYIEI AIKQCRSSGI DCKIHGLILL GRIRAEEEDL AAVPFLASDN EEEEDEKGNS
GSLIRKKAAG LESAATIRTK VFVWGLNDKD QLGGLKGSKI KVPSFSETLS ALNVVQVAGG
SKSLFAVTVE GKVYACGEAT NGRLGLGISS GTVPIPRQIT ALSSYVVKKV AVHSGGRHAT
ALTVDGKVFS WGEGDDGKLG HFSRMNCDKP RLIEALKTKR IRDIACGSSH SAALTSSGEL
YTWGLGEYGR LGHGDNTTQL KPKMVKVLLG HRVIQVACGS RDAQTLALTD EGLVFSWGDG
DFGKLGRGGS EGCNIPQNIE RLNGQGVCQI ECGAQFSLAL TKSGVVWTWG KGDYFRLGHG
SDVHVRKPQV VEGLRGKKIV HVAVGALHCL AVTDSGQVYA WGDNDHGQQG NGTTTVNRKP
TLVQGLEGQK ITRVACGSSH SVAWTTVDVA TPSVHEPVLF QTARDPLGAS YLGVPSDADS
SAASNKISGA SNSKPNRPSL AKILLSLDGN LAKQQALSHI LTALQIMYAR DAVVGALMPA
AMIAPVECPS FSSAAPSDAS AMASPMNGEE CMLAVDIEDR LSPNPWQEKR EIVSSEDAVT
PSAVTPSAPS ASARPFIPVT DDLGAASIIA ETMTKTKEDV ESQNKAAGPE PQALDEFTSL
LIADDTRVVV DLLKLSVCSR AGDRGRDVLS AVLSGMGTAY PQVADMLLEL CVTELEDVAT
DSQSGRLSSQ PVVVESSHPY TDDTSTSGTV KIPGAEGLRV EFDRQCSTER RHDPLTVMDG
VNRIVSVRSG REWSDWSSEL RIPGDELKWK FISDGSVNGW GWRFTVYPIM PAAGPKELLS
DRCVLSCPSM DLVTCLLDFR LNLASNRSIV PRLAASLAAC AQLSALAASH RMWALQRLRK
LLTTEFGQSI NINRLLGEND GETRALSFTG SALAALVKGL PEALQRQFEY EDPIVRGGKQ
LLHSPFFKVL VALACDLELD TLPCCAETHK WAWFRRYCMA SRVAVALDKR TPLPRLFLDE
VAKKIRELMA DSENMDVLHE SHDIFKREQD EQLVQWMNRR PDDWTLSAGG SGTIYGWGHN
HRGQLGGIEG AKVKVPTPCE ALATLRPVQL IGGEQTLFAV TADGKLYATG YGAGGRLGIG
GTESVSTPTL LESIQHVFIK KVAVNSGGKH CLALSSEGEV YSWGEAEDGK LGHGNRSPCD
RPRVIESLRG IEVVDVAAGG AHSACVTAAG DLYTWGKGRY GRLGHSDSED QLKPKLVEAL
QGHRVVDIAC GSGDAQTLCL TDDDTVWSWG DGDYGKLGRG GSDGCKVPMK IDSLTGLGVV
KVECGSQFSV ALTKSGAVYT WGKGDYHRLG HGSDDHVRRP RQVQGLQGKK VIAIATGSLH
CVCCTEDGEV YTWGDNDEGQ LGDGTTNAIQ RPRLVAALQG KKVNRVACGS AHTLAWSTSK
PASAGKLPAQ VPMEYNHLQE IPIIALRNRL LLLHHLSELF CPCIPMFDLE GSLDETGLGP
SVGFDTLRGI LISQGKEAAF RKVVQATMVR DRQHGPVVEL NRIQVKRSRS KGGLAGPDGT
KSVFGQMCAK MSSFGPDSLL LPHRVWKVKF VGESVDDCGG GYSESIAEIC EELQNGLTPL
LIVTPNGRDE SGANRDCYLL SPAARAPVHS SMFRFLGVLL GIAIRTGSPL SLNLAEPVWK
QLAGMSLTIA DLSEVDKDFI PGLMYIRDNE ATSEEFEAMS LPFTVPSASG QDIQLSSKHT
HITLDNRAEY VRLAINYRLH EFDEQVAAVR EGMARVVPVP LLSLFTGYEL ETMVCGSPDI
PLHLLKSVAT YKGIEPSASL IQWFWEVMES FSNTERSLFL RFVWGRTRLP RTIADFRGRD
FVIQVLDKYN PPDHFLPESY TCFFLLKLPR YSCKQVLEEK LKYAIHFCKS IDTDDYARIA
LTGEPAADDS SDDSDNEDVD SFASDSTQDY LTGH
//

MIM 227220
*RECORD*
*FIELD* NO
227220
*FIELD* TI
#227220 SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 1; SHEP1
;;SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES;;
read moreSKIN/HAIR/EYE PIGMENTATION 1, BLUE/BROWN EYES;;
SKIN/HAIR/EYE PIGMENTATION 1, BLOND/BROWN HAIR;;
EYE COLOR, BROWN/BLUE;;
EYE COLOR, BLUE/NONBLUE;;
EYE COLOR 3; EYCL3;;
BROWN EYE COLOR 2; BEY2;;
HAIR COLOR 3; HCL3
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
variants of the OCA2 gene (611409) play a role in determining blue
versus nonblue eye color, and blond versus brown hair. Noncoding
variants in the HERC2 gene (605837) 200 kb downstream of OCA2 that are
thought to affect OCA2 expression have also been associated.

DESCRIPTION

- Genetic Heterogeneity of Variation in Skin/Hair/Eye Pigmentation

Multiple genes influence normal human skin, hair, and/or eye
pigmentation. Pigmentation phenotypes influenced by variation in the
OCA2 gene are termed SHEP1. The SHEP2 association (266300) is determined
by variation at the MC1R locus (155555) and describes a phenotype
predominantly characterized by red hair and fair skin. SHEP3 (601800)
encompasses pigment variation influenced by the TYR gene (606933); SHEP4
(113750), that influenced by the SLC24A5 gene (609802). Variation in the
SLC45A2 (606202) and SLC24A4 (609840) genes result in the phenotypic
associations SHEP5 (227240) and SHEP6 (210750), respectively. Sequence
variation thought to affect expression of KITLG (184745) results in the
SHEP7 (611664) phenotypic association, and SHEP8 (611724) has been
associated with single-nucleotide polymorphisms (SNPs) at chromosome
6p25.3. Polymorphism in the 3-prime-untranslated region of the ASIP gene
(600201) influences the SHEP9 association (611742). The SHEP10
association (612267) comprises variation in the TPCN2 gene (612163), and
SHEP11 (612271) is associated with polymorphism near the TYRP1 gene
(115501).

CLINICAL FEATURES

Pigmentation of hair, eye, and skin is among the most visible examples
of human phenotypic variation, with a broad normal range that is subject
to substantial geographic stratification. Pigmentation in human tissues
is attributable to the number, type, and cellular distribution of
melanosomes (subcellular compartments produced by melanocytes that
synthesize and store the light-absorbing polymer melanin) (Sulem et al.,
2007). Variation in pigmentation among individuals is thought to be
caused by biochemical differences that affect the number of melanosomes
produced, the type of melanin synthesized (either black-brown eumelanin
or red-yellow pheomelanin), and the size and shape of the melanosomes.
The key physiologic role of skin pigmentation seems to be to absorb
ultraviolet radiation (UVR). This protective role must be weighted
against the reduced amount of UVR available for the synthesis of vitamin
D3. It is generally believed that the geographic distribution of human
skin pigmentation reflects a history of adaptation to latitude-dependent
levels of UVR, with individuals tending to have lighter pigmentation
with increasing distance from the equator (Relethford, 1997). The
majority of variation in human eye and hair color is found among
individuals of European ancestry, with most other human populations
fixed for brown eyes and black hair (Sulem et al., 2007). Stokowski et
al. (2007) cited studies suggesting that the genetic factors influencing
lighter pigmentation in Europeans may be far different from the
mechanism for lighter pigmentation in East Asians (Relethford, 1997;
Norton et al., 2006; Myles et al., 2007). Given the direct correlation
between skin pigmentation and incident UV exposure, it has long been
postulated that it is a trait under intense selective pressure
(Stokowski et al., 2007). Pigmentary mutants in model organisms and
human disorders of pigmentation have been the main source for the
discovery of genes involved in skin color. More than 100 pigmentation
genes have been identified in mouse alone, most with identified human
orthologs, and at least 18 genes had been implicated in human albinism.

MAPPING

Eiberg and Mohr (1996) sought the location of the BEY2 locus for brown
eye color through an inquiry using data on eye color and hair color in
832 families from the Copenhagen area. By exclusion mapping with 80
markers in 120 segregating families and 290 markers in 5 segregating
families, they obtained some indication of a locus BEY2 for brown eye
color on chromosome 15. For possible confirmation, they selected a total
of 45 families from their DNA bank segregating for BEY. All these were
tested for chromosome 15 markers in the area between D15S11 and CYP19
(107910). They found a strong indication of linkage with the DNA
polymorphism D15S165 and with flanking markers D15S156 and D15S144. A
multipoint lod score of 32.2 was obtained for location in this interval.
These markers had been assigned to the 15q11-q21 region.

Eiberg and Mohr (1996) obtained a lod score of 9.93 at theta (M = Z) =
0.10 for linkage of a locus for brown hair color (HCL3) to a locus for
brown eye color (BEY2) that they mapped to 15q11-q21. The studies were
done in 45 families from the Copenhagen area segregating for brown eye
color. They found 56 matings informative for brown eye color and hair
color; in 51 of these families the 2 traits were inherited together (in
cis), while in 5 families the 2 traits were separated when transmitted
to the offspring (in trans). They analyzed 3 of the 'trans' families and
found that BEY2 and HCL3 segregated with chromosome 15 markers. This
supported the assumption of linkage disequilibrium between BEY2 and
HCL3, due presumably to recent immigration of people with brown hair and
brown eye color, as an explanation for the excess of the apparent phase
cis. There was an association between brown eye color and brown hair
color in the 45 selected families; among 46 parents with brown eye color
44 had brown hair color, while among 44 spouses with blue eye color only
26 had brown hair color. Eiberg and Mohr (1996) suggested the P gene
(OCA2; 611409), which resides in the 15q11-q21 region and which is the
site of mutations causing type II oculocutaneous albinism (203200), as a
candidate gene for brown eye and hair color.

MOLECULAR GENETICS

Two OCA2 coding region variant alleles, arg305 to trp (R305W;
611409.0011) and arg419 to gln (R419Q; 611409.0012), were shown to be
associated with brown and green/hazel eye colors, respectively (Rebbeck
et al., 2002; Jannot et al., 2005), and blue eye color was also shown to
be linked to the OCA2 locus through use of microsatellite (Posthuma et
al., 2006; Frudakis et al., 2003) and single-nucleotide polymorphism
(SNP) (International HapMap Consortium, 2005) markers.

Duffy et al. (2007) found that 3 SNPs in intron 1 of the OCA2 gene have
the highest statistical association with blue eye color. Moreover, these
are found in a tight linkage disequilibrium block, with the TGT
haplotype 1 (611409.0013) representing 78.4% of alleles in their sample.
Given that nonbrown eye colors are found at high frequency only in white
populations, Duffy et al. (2007) considered it notable that haplotype 1
was found at 82.5% in Europeans and at only minor frequencies (7.4% in
those of African and 12.1% in those of East Asian descent) in others,
suggesting strong positive selection for TGT in Europeans. The TGT/TGT
diplotype of OCA2 was found in 62.2% of samples and was the major
genotype seen to modify eye color, with a frequency of 0.905 in blue or
green compared with only 0.095 in brown eye color. This genotype was
also at highest frequency in subjects with light brown hair and was more
frequent in fair and medium skin types, consistent with the TGT
haplotype acting as a recessive modifier of lighter pigmentary
phenotypes. Duffy et al. (2007) found only minor population impact of
the R305W and R419Q associated with nonblue eyes, as contrasted with the
tight linkage of the major TGT haplotype within intron 1 of OCA2 with
blue eye color and lighter hair and skin tones, which suggested that
differences within the 5-prime proximal regulatory control region of the
OCA2 gene alter expression or mRNA transcript levels and may be
responsible for these associations.

Among 2,986 Icelanders, Sulem et al. (2007) carried out a genomewide
association scan for variants associated with hair and eye pigmentation,
skin sensitivity to sun, and freckling. The most closely associated SNPs
from 6 regions were then tested for replication in a second sample of
2,718 Icelanders and a sample of 1,214 Dutch. A 1-Mb region on
chromosome 15 overlapping the OCA2 gene and containing 16 SNPs showed
association with blue versus brown eyes, blue versus green eyes, blond
versus brown hair, or some combination of these traits in the Icelandic
sample that reached genomewide significance. The 3 common variants in
intron 1 of OCA2, dbSNP rs7495174, dbSNP rs4778241, and dbSNP rs4778138,
reported by Duffy et al. (2007) as strongly associated with skin, hair,
and eye pigmentation in populations of European ancestry, were among the
16 detected in the genomewide scan. However, the SNP that showed the
strongest association was dbSNP rs1667394 (OR = 35.42, P = 1.4 x
10(-124) for blue versus brown eyes; OR = 7.02, P = 5.1 x 10(-25) for
blue versus green eyes; OR = 5.62, P = 4.4 x 10(-16) for blond versus
brown hair). This SNP is located 200 kb downstream of OCA2, within
intron 4 of the HERC2 gene (605837.0001). Given the established
relationship between OCA2 and pigmentation, Sulem et al. (2007)
considered it unlikely that the association signal provided by this SNP
was due to a functional effect on HERC2. Rather, they suggested that
perhaps sequence variation in the introns of HERC2 affects the
expression of OCA2, or that functional variants exist within OCA2 that
correlate with dbSNP rs1667394.

In European populations, Kayser et al. (2008) and Sturm et al. (2008)
identified variants in introns of the HERC2 gene (605837.0002,
605837.0003) that were better predictors of blue eye color than were the
variants found by Duffy et al. (2007) in intron 1 of OCA2 (611409.0013).
Sturm et al. (2008) identified the R419Q variant of OCA2 (611409.0012)
as a penetrance modifier of the HERC2 variant dbSNP rs12913832
(605837.0003) and of the risk of malignant melanoma.

In a 3-generation Danish family segregating blue and brown eye color,
Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate
region within the HERC2 gene. Further studies of SNPs within this region
among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs,
dbSNP rs1129038 and the strongly conserved dbSNP rs12913832, that showed
significant associations with the blue-eyed phenotype (p = 6.2 x
10(-46)). A common founder haplotype containing these SNPs was
identified among blue-eyed persons from Denmark, Turkey, and Jordan.

In a study of eye color variation in a cohort of 718 individuals of
European descent, Pospiech et al. (2011) used multifactor dimensionality
reduction and logistic regression to examine gene-gene interactions
based on SNPs in 11 known pigmentation genes. Significant interaction
effects were found for 3 gene pairs: dbSNP rs12913832 in HERC2 and dbSNP
rs1800407 in OCA2 for hazel versus nonhazel and for green versus
nongreen eye color; dbSNP rs12913832 in HERC2 and dbSNP rs12896399 in
SLC24A4 for blue versus nonblue; and dbSNP rs12913832 in HERC2 and dbSNP
rs1408799 in TYRP1 for green versus nongreen color. The interaction of
the HERC2 and OCA2 genes and the HERC2 and TYRP1 genes showed a
synergistic effect for green eye color. The findings confirmed that the
HERC2 and OCA2 genes have a predominant role in eye color inheritance.

Donnelly et al. (2012) genotyped 3,432 individuals from 72 populations
for 21 SNPs in the OCA2-HERC2 region, and found that blue-eye-associated
alleles in all 3 haplotypes that previously had been associated with eye
pigmentation in Europeans occurred at high frequencies in Europe;
however, 1 was restricted to Europe and surrounding regions, whereas the
other 2 were found at moderate to high frequencies throughout the world.
Their data suggested that the TG allele of the haplotype restricted to
Europe, consisting of the SNPs dbSNP rs1129038 and dbSNP rs12913832 and
which they designated 'BEH2,' was the best marker for blue eyes.

HISTORY

Iris color was one of the first human traits used in investigating
mendelian inheritance in humans. Davenport and Davenport (1907) outlined
what was long taught in schools as a beginner's guide to genetics, that
brown eye color is always dominant to blue, with 2 blue-eyed parents
always producing a blue-eyed child, never one with brown eyes. As with
many physical traits, the simplistic model does not convey the fact that
eye color is inherited as a polygenic, not as a monogenic, trait (Sturm
and Frudakis, 2004). The early view that blue is a simple recessive has
been repeatedly shown to be wrong by observation of brown-eyed offspring
of 2 blue-eyed parents. My monozygotic twin brother and I, brown-eyed,
had blue-eyed parents and blue-eyed sibs (VAM). Blue-eyed offspring from
2 brown-eyed parents is a more frequent finding.

In some Norwegian families, Gedde-Dahl (1981) found diffusely brown eyes
or centrally brown eyes segregating as simple dominant traits,
symbolized BEY1. Possible linkage to Km (Inv) and to Co was found,
suggesting the order Jk--Km--BEY1--Co. (Co and Km are not measurably
linked.)

Gedde-Dahl et al. (1982) found positive lod scores between brown eye
color BEY1 (later described as central brown eye color) and the blood
groups Colton (CO; 110450, which maps to chromosome 7) and Kidd (JK;
111000, which maps to chromosome 18, Eiberg (1997)). Another phenotype,
green eye color (GEY; see 601800), mapped to chromosome 19 by linkage to
secretor (SE; 182100) and Lutheran (LU; 111150). A gene for brown hair
color segregated with GEY (maximum lod = 5.6 at theta = 0.010) in the
data of Eiberg and Mohr (1987).

Eiberg and Mohr (1987) found a lod score of 5.06 for linkage of GEY to
brown hair color (BRHC, HCL1). Of interest is the fact that 6 loci on
chromosome 19 in man have their homologs on chromosome 7 in the mouse.
Chromosome 7 carries at least 3 'pigment loci,' namely, ruby-2 (ru-2),
pink-eyed dilution (p; see 611409), and albino (c).

Eiberg (1997) stated that they found both cis and trans segregations of
green eye color and brown hair color in families chosen primarily for
segregation for green eye color.

*FIELD* SA
Rufer et al. (1970)
*FIELD* RF
1. Davenport, G. C.; Davenport, C. B.: Heredity of eye color in man. Science 26:
589-592, 1907.

2. Donnelly, M. P.; Paschou, P.; Grigorenko, E.; Gurwitz, D.; Barta,
C.; Lu, R.-B.; Zhukova, O. V.; Kim, J.-J.; Siniscalco, M.; New, M.;
Li, H.; Kajuna, S. L. B.; Manolopoulos, V. G.; Speed, W. C.; Pakstis,
A. J.; Kidd, J. R.; Kidd, K. K.: A global view of the OCA2-HERC2
region and pigmentation. Hum. Genet. 131: 683-696, 2012.

3. Duffy, D. L.; Montgomery, G. W.; Chen, W.; Zhao, Z. Z.; Le, L.;
James, M. R.; Hayward, N. K.; Martin, N. G.; Sturm, R. A.: A three-single-nucleotide
polymorphism haplotype in intron 1 of OCA2 explains most human eye-color
variation. Am. J. Hum. Genet. 80: 241-252, 2007.

4. Eiberg, H.: Personal Communication. Copenhagen, Denmark 3/25/1997.

5. Eiberg, H.: Personal Communication. Copenhagen, Denmark 5/9/1997.

6. Eiberg, H.; Mohr, J.: Major genes of eye color and hair color
linked to LU and SE. Clin. Genet. 31: 186-191, 1987.

7. Eiberg, H.; Mohr, J.: Assignment of genes coding for brown eye
colour (BEY2) and brown hair colour (HCL3) on chromosome 15q. Europ.
J. Hum. Genet. 4: 237-241, 1996.

8. Eiberg, H.; Troelsen, J.; Nielsen, M.; Mikkelsen, A.; Mengel-From,
J.; Kjaer, K. W.; Hansen, L.: Blue eye color in humans may be caused
by a perfectly associated founder mutation in a regulatory element
located within the HERC2 gene inhibiting OCA2 expression. Hum. Genet. 123:
177-187, 2008.

9. Frudakis, T.; Thomas, M.; Gaskin, Z.; Venkateswarlu, K.; Chandra,
K. S.; Ginjupalli, S.; Gunturi, S.; Natrajan, S.; Ponnuswamy, V. K.;
Ponnuswamy, K. N.: Sequences associated with human iris pigmentation. Genetics 165:
2071-2083, 2003.

10. Gedde-Dahl, T., Jr.: Personal Communication. Oslo, Norway
6/1981.

11. Gedde-Dahl, T., Jr.; Olaisen, B.; Siverts, A.; Wilhelmy, M.:
Support for synteny of PTC-K with Jk-IGK-BEY1-Co? (Abstract) Cytogenet.
Cell Genet. 32: 278 only, 1982.

12. International HapMap Consortium: A haplotype map of the human
genome. Nature 437: 1299-1320, 2005.

13. Jannot, A.-S.; Meziani, R.; Bertrand, G.; Gerard, B.; Descamps,
V.; Archimbaud, A.; Picard, C.; Ollivaud, L.; Basset-Seguin, N.; Kerob,
D.; Lanternier, G.; Lebbe, C.; Saiag, P.; Crickx, B.; Clerget-Darpoux,
F.; Grandchamp, B.; Soufir, N.; Melan-Cohort: Allele variations
in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic
susceptibility to melanoma. Europ. J. Hum. Genet. 13: 913-920, 2005.

14. Kayser, M.; Liu, F.; Janssens, A. C. J. W.; Rivadeneira, F.; Lao,
O.; van Duijn, K.; Vermeulen, M.; Arp, P.; Jhamai, M. M.; van IJcken,
W. F. J.; den Dunnen, J. T.; Heath, S.; and 10 others: Three genome-wide
association studies and a linkage analysis identify HERC2 as a human
iris color gene. Am. J. Hum. Genet. 82: 411-423, 2008. Note: Erratum:
Am. J. Hum. Genet. 82: 801 only, 2008.

15. Myles, S.; Somel, M.; Tang, K.; Kelso, J.; Stoneking, M.: Identifying
genes underlying skin pigmentation differences among human populations. Hum.
Genet. 120: 613-621, 2007.

16. Norton, H. L.; Kittles, R. A.; Parra, E.; McKeigue, P.; Mao, X.;
Cheng, K.; Canfield, V. A.; Bradley, D. G.; McEvoy, B.; Shriver, M.
D.: Genetic evidence for the convergent evolution of light skin in
Europeans and East Asians. Molec. Biol. Evol. 24: 710-722, 2006.

17. Pospiech, E.; Draus-Barini, J.; Kupiec, T.; Wojas-Pelc, A.; Branicki,
W.: Gene-gene interactions contribute to eye colour variation in
humans. J. Hum. Genet. 56: 447-455, 2011.

18. Posthuma, D.; Visscher, P. M.; Willemsen, G.; Zhu, G.; Martin,
N. G.; Slagboom, P. E.; de Geus, E. J.; Boomsma, D. I.: Replicated
linkage for eye color on 15q using comparative ratings of sibling
pairs. Behav. Genet. 36: 12-17, 2006.

19. Rebbeck, T. R.; Kanetsky, P. A.; Walker, A. H.; Holmes, R.; Halpern,
A. C.; Schuchter, L. M.; Elder, D. E.; Guerry, D.: P gene as an inherited
biomarker of human eye color. Cancer Epidemiol. Biomarkers Prev. 11:
782-784, 2002.

20. Relethford, J. H.: Hemispheric difference in human skin color. Am.
J. Phys. Anthrop. 104: 449-457, 1997.

21. Rufer, V.; Bauer, J.; Soukup, F.: On the heredity of eye colour. Acta
Univ. Carol. Med. 16: 429-434, 1970.

22. Stokowski, R. P.; Pant, P. V. K.; Dadd, T.; Fereday, A.; Hinds,
D. A.; Jarman, C.; Filsell, W.; Ginger, R. S.; Green, M. R.; van der
Ouderaa, F. J.; Cox, D. R.: A genomewide association study of skin
pigmentation in a South Asian population. Am. J. Hum. Genet. 81:
1119-1132, 2007.

23. Sturm, R. A.; Duffy, D. L.; Zhao, Z. Z.; Leite, F. P. N.; Stark,
M. S.; Hayward, N. K.; Martin, N. G.; Montgomery, G. W.: A single
SNP in an evolutionary conserved region within intron 86 of the HERC2
gene determines human blue-brown eye color. Am. J. Hum. Genet. 82:
424-431, 2008.

24. Sturm, R. A.; Frudakis, T. N.: Eye color: portals into pigmentation
genes and ancestry. Trends Genet. 20: 327-332, 2004.

25. Sulem, P.; Gudbjartsson, D. F.; Stacey, S. N.; Helgason, A.; Rafnar,
T.; Magnusson, K. P.; Manolescu, A.; Karason, A.; Palsson, A.; Thorleifsson,
G.; Jakobsdottir, M.; Steinberg, S.; and 13 others: Genetic determinants
of hair, eye and skin pigmentation in Europeans. Nature Genet. 39:
1443-1452, 2007.

*FIELD* CS

Eyes:
Blue color recessive to brown

Inheritance:
Autosomal recessive at BEY locus;
Eye color probably polygenic

*FIELD* CN
Marla J. F. O'Neill - updated: 9/18/2012
Cassandra L. Kniffin - updated: 4/11/2008
Anne M. Stumpf - reorganized: 1/10/2008
Victor A. McKusick - updated: 2/8/2007
Victor A. McKusick - updated: 5/15/1997

*FIELD* CD
Victor A. McKusick: 12/16/1986

*FIELD* ED
terry: 11/13/2012
alopez: 9/18/2012
joanna: 11/14/2011
carol: 10/13/2011
ckniffin: 9/13/2011
alopez: 9/4/2008
terry: 6/6/2008
wwang: 4/18/2008
ckniffin: 4/11/2008
alopez: 4/4/2008
alopez: 4/3/2008
alopez: 2/18/2008
alopez: 1/18/2008
alopez: 1/17/2008
alopez: 1/16/2008
alopez: 1/10/2008
carol: 9/12/2007
terry: 8/9/2007
alopez: 2/9/2007
terry: 2/8/2007
alopez: 3/18/2004
carol: 6/15/1999
dkim: 7/21/1998
mark: 5/15/1997
alopez: 5/13/1997
terry: 5/6/1997
mimadm: 2/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
marie: 12/16/1986

MIM 605837
*RECORD*
*FIELD* NO
605837
*FIELD* TI
*605837 HECT DOMAIN AND RCC1-LIKE DOMAIN 2; HERC2
*FIELD* TX

DESCRIPTION

HERC2 shuttles between the nucleus and cytoplasm and functions as an E3
read moreubiquitin ligase for the ubiquitination and degradation of target
proteins (Wu et al., 2010), as an activator of other E3 ubiquitin
ligases (Kuhnle et al., 2011), and as an adaptor for assembly of DNA
damage response proteins (Bekker-Jensen et al., 2010).

For background information on the HERC gene family, see HERC1 (605109).

CLONING

Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830)
result from deletions and loss of function of oppositely imprinted genes
located within the proximal 2 Mb of the 15q11-q13 region. Low-copy
repeat elements have been identified in the vicinity of the 3 deletion
breakpoint hotspots using molecular and cytologic methods. Using
positional cloning from low-copy repeats flanking 15q11-q13, genomic
sequence analysis, EST database searching, PCR, and long-range RT-PCR,
Ji et al. (1999) obtained a cDNA encoding HERC2, which is identical to a
partial cDNA, KIAA0393, identified by Nagase et al. (1997). Sequence
analysis predicted that the 4,834-amino acid protein, which is 95%
identical and 99% similar to the mouse protein, contains 3 RCC1-like
domains (RLDs); a putative ZZ-type zinc finger motif with 6 conserved
cysteines and 2 outlying histidine residues; a C-terminal HECT or E3
ubiquitin ligase (see UBE3A; 601623) domain; and several potential
phosphorylation sites. The overall structure is similar to that of
HERC1, although HERC1 has only 2 RLDs and no zinc finger motif. The
C-terminal region of HERC2 resembles that of HERC3 (605200). Northern
blot analysis revealed ubiquitous expression of a 15.5-kb HERC2
transcript, with high levels in fetal tissues and adult skeletal muscle,
heart, ovary, testis, and brain.

Using SDS-PAGE, Bekker-Jensen et al. (2010) found that endogenous human
HERC2 had an apparent molecular mass of 500 kD.

MAPPING

Nagase et al. (1997) mapped the HERC2 gene, which they called KIAA0393,
to chromosome 15 using radiation hybrid analysis. By Southern blot
analysis of YACs and radiation hybrid analysis, Ji et al. (1999) mapped
the HERC2 gene to 15q11-q13, very close to the P gene (OCA2; 611409).
Southern blot analysis of PWS and AS patients resulted in HERC2 signals
of 50% intensity compared with controls. The mouse Herc2 gene maps to
chromosome 7C, within the juvenile development and fertility-2 (jdf2)
interval (Ji et al., 1999).

Kayser et al. (2008) identified the HERC2 gene within a region on
chromosome 15q13.1 linked to determination of human iris color.

GENE FUNCTION

RNF8 (611685) is an E3 ubiquitin ligase that interacts with the E2
ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679) and catalyzes
formation of lys63-linked ubiquitin chains on histone H2A (see 613499)
flanking sites of DNA damage. Using mass spectrometric analysis,
Bekker-Jensen et al. (2010) found that endogenous HERC2 affinity
purified with RNF8 from HEK293T cells. RNF8 interacted with the
C-terminal HECT domain of HERC2, and phosphorylation of thr4827 within
the HECT domain was required for the interaction. Association of HERC2
with RNF8 increased following exposure to DNA damage-inducing ionizing
radiation. The DNA damage response kinases ATM (607585), ATR (601215),
and DNAPK (see 600899) also interacted with the C terminus of HERC2, and
inhibition of these kinases interfered with the RNF8-HERC2 association
in an additive manner. HERC2 also interacted in a ternary complex with
MDC1 (607593) and RNF8, and all 3 proteins accumulated at sites of DNA
double-strand breaks. Depletion of HERC2 in HEK293T cells did not impair
accumulation of RNF8 and MDC1 at sites of DNA damage, but it caused
failure to recruit UBC13 to RNF8, leading to failure of histone H2A
polyubiquitination and accumulation of downstream DNA damage repair and
signaling factors.

BRCA1 (113705) maintains genomic stability by functioning in DNA damage
repair, cell cycle checkpoint, and apoptosis. BRCA1 forms a
heterodimeric E3 ubiquitin ligase with BARD1 (601593), and loss of this
interaction results in BRCA1 degradation. Wu et al. (2010) found that
HERC2 countered the stabilizing effect of BARD1 on BRCA1 and caused
BRCA1 degradation. The HECT domain of HERC2 interacted with and caused
ubiquitination of an N-terminal degradation domain of BRCA1, targeting
BRCA1 for degradation. The reaction depended on cys4762 within the
catalytic ubiquitin-binding site of HERC2. The HERC2-BRCA1 interaction
and BRCA1 degradation were maximal during S phase in synchronized HeLa
cells and rapidly diminished as cells entered G2-M. Wu et al. (2010)
concluded that HERC2 is an E3 ligase that targets BRCA1 for degradation
during S phase of the cell cycle.

Using yeast 2-hybrid analysis and coprecipitation analysis of
cotransfected and endogenous proteins, Kuhnle et al. (2011) found that
HERC2 interacted with the 852-amino acid isoform of the E3 ubiquitin
ligase E6AP (UBE3A; 601623). Domain analysis revealed that the central
RLD2 domain of HERC2 and a domain near the N terminus of E6AP were
required for the interaction. Full-length HERC2 or the isolated RLD2
domain of HERC2 stimulated the E3 activity of E6AP in autoubiquitination
and in ubiquitination of an E6AP substrate. Stimulation of E6AP did not
require catalytically active HERC2.

MOLECULAR GENETICS

- Skin, Hair, Eye Pigmentation

In a large genomewide scan to identify variants associated with hair and
eye pigmentation, skin sensitivity to sun, and freckling, Sulem et al.
(2007) identified a single-nucleotide polymorphism (SNP), dbSNP
rs1667394, in intron 4 of the HERC2 gene (605837.0001) that was
associated with blue eye color and blond hair. Of several SNPs within a
1-Mb region of linkage overlapping the OCA2 gene (611409), dbSNP
rs1667394 had the strongest association with pigmentation. Given the
established relationship between OCA2 and pigmentation, Sulem et al.
(2007) considered it unlikely that the association signal provided by
this SNP was due to a functional effect on HERC2.

In 3 independent genomewide association studies and a genomewide linkage
study involving over 2,600 persons from the Netherlands, Kayser et al.
(2008) found that the chromosome 15q13.1 region is the predominant
region involved in human iris color. There were no other regions showing
consistent genomewide evidence for association and linkage to iris
color. SNPs in the HERC2 gene and, to a lesser extent, in the
neighboring OCA2 gene (611409) were independently associated with iris
color variation. Kayser et al. (2008) found that HERC2 dbSNP rs916977
(605837.0002) showed a clinal allele distribution across 23 European
populations that was significantly correlated to iris color variation.
They suggested that genetic variants regulating expression of the OCA2
gene exist in the HERC2 gene or, alternatively, with the 11.7 kb of
sequence between OCA2 and HERC2, and that most iris color variation in
Europeans is explained by those 2 genes. They further suggested that
testing markers in the HERC2-OCA2 region may be useful in forensic
applications to predict eye color phenotypes of unknown persons of
European genetic origin.

Duffy et al. (2007) demonstrated that haplotypes of 3 SNPs within the
first intron of the OCA2 gene are strongly associated with variation in
human eye color. Following up on this study, Sturm et al. (2008)
described additional fine association mapping of eye color SNPs in the
intergenic region upstream of OCA2 and within the neighboring HERC2
gene. They screened an additional 92 SNPs in 300 to 3,000 European
individuals and found that a single SNP in intron 86 of HERC2, dbSNP
rs12913832 (605837.0003), predicted eye color significantly better than
their previous best OCA2 haplotype. Comparison of sequence alignments of
multiple species showed that this SNP lies in the center of a short
highly conserved sequence and that the blue eye-associated allele
(frequency 78%) breaks up this conserved sequence, part of which forms a
consensus binding site for the helicase-like transcription factor (HLTF;
603257). Sturm et al. (2008) also demonstrated that the OCA2 coding SNP
R419Q (611409.0012) acts as a penetrance modifier of this new HERC2 SNP
for eye color and, somewhat independently, of melanoma risk. Sturm et
al. (2008) concluded that the conserved region around dbSNP rs12913832
(the SNP in intron 86 of HERC2) represents a regulatory region
controlling constitutive expression of OCA2 and that the C allele at
this SNP leads to decreased expression of OCA2, particularly within iris
melanocytes, which they postulated to be the ultimate cause of blue eye
color.

In a 3-generation Danish family segregating blue and brown eye color,
Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate
region within the HERC2 gene. Further studies of SNPs within this region
among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs,
dbSNP rs1129038 and the strongly conserved dbSNP rs12913832, that showed
significant associations with the blue-eyed phenotype (p = 6.2 x
10(-46)). A common founder haplotype containing these SNPs was
identified among blue-eyed persons from Denmark, Turkey, and Jordan. In
vitro functional expression studies in human colon carcinoma cells
showed that what the authors referred to as the 'G' allele of dbSNP
rs12913832, present in blue-eyed individuals, had an inhibitory effect
on OCA2 promoter activity. In the 3-generation Danish family, blond hair
color was associated with lighter brown/blue eyes and brown hair color
was associated with brown eyes. Hair color also associated with several
SNPs in the HERC2 gene. However, linkage analysis also implicated a
region associated with hair color on chromosome 14 (lod score of 4.21 at
D14S72), close to the RABGGTA gene (601905).

Donnelly et al. (2012) genotyped 3,432 individuals from 72 populations
for 21 SNPs in the OCA2-HERC2 region, and found that blue-eye-associated
alleles in all 3 haplotypes that previously had been associated with eye
pigmentation in Europeans occurred at high frequencies in Europe;
however, 1 was restricted to Europe and surrounding regions, whereas the
other 2 were found at moderate to high frequencies throughout the world.
Their data suggested that the TG allele of the haplotype restricted to
Europe, consisting of the SNPs dbSNP rs1129038 and dbSNP rs12913832 and
which they designated 'BEH2,' was the best marker for blue eyes.

- Autosomal Recessive Mental Retardation 38

In 7 patients of Amish or mixed Amish/Mennonite descent with autosomal
recessive mental retardation-38 (MRT38; 615516), Puffenberger et al.
(2012) identified a homozygous missense mutation in the HERC2 gene
(P594L; 605837.0004). The mutation was found by a combination of
homozygosity mapping and exome sequencing. Cellular transfection studies
showed that the mutant protein was less stable than wildtype and had a
diffuse cytosolic localization with the formation of abnormal
aggregates. Decreased abundance and/or activity of HERC2 could produce a
toxic loss of E3 ubiquitin ligase activity, leading to decreased
degradation of ARC (612461) and decreased postsynaptic glutamatergic
AMPA receptor density. Puffenberger et al. (2012) noted that this
pathophysiologic mechanism is similar to that thought to underlie
Angelman syndrome (105830), which results from loss of function of the
UBE3A gene (601623) on chromosome 15q11. The individuals with MRT38 had
some features similar to those of AS.

ANIMAL MODEL

Ji et al. (1999) identified splice junction mutations in the Herc2 gene
in chemically-induced mouse jdf2 mutant alleles. The mutations led to
exon skipping and premature termination, resulting in neuromuscular
secretory vesicle defects, sperm acrosome defects, and juvenile
lethality in jdf2 mice.

*FIELD* AV
.0001
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
SKIN/HAIR/EYE PIGMENTATION 1, BLOND/BROWN HAIR, INCLUDED
HERC2, IVS4, A/G

In a discovery sample of 2,986 Icelanders and replication samples of
2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association
of the A allele of dbSNP rs1667394 with blue versus brown eyes (OR =
35.42, P = 1.4 x 10(-124)), with blue versus green eyes (OR = 7.02, P =
5.1 x 10(-25)), and with blond versus brown hair (OR = 5.62, P = 4.4 x
10(-16)). Although the dbSNP rs1667394 variant resides in the HERC2
gene, Sulem et al. (2007) considered it unlikely that the association
signal provided by this SNP was due to a functional effect on HERC2.
Because of the established relationship between the OCA2 gene (611409)
and blue eye color and lighter hair and skin tones (227220), the authors
suggested that perhaps sequence variation in the introns of HERC2
affects the expression of OCA2, or that functional variants exist within
OCA2 that correlate with dbSNP rs1667394.

.0002
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
HERC2, IVS12, C/T

In 3 independent genomewide association studies of a total of 1,406
persons and a genomewide linkage study of 1,292 relatives, all from the
Netherlands, Kayser et al. (2008) found that the HERC2 variant dbSNP
rs916977 showed a gradient-wise (clinal) allele distribution across 23
European populations that was significantly correlated to iris color
variation (227220), with the C allele, associated with blue eyes, being
more common in northern Europe and the T allele, associated with brown
eyes, more common in southern Europe. Analysis of dbSNP rs916977
together with the 3 SNPs in intron 1 of the OCA2 gene identified by
Duffy et al. (2007) (611409.0013) revealed significant genomewide
association for only the HERC2 SNP (P = 3.53 x 10(-18)).

.0003
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
HERC2, IVS86, C/T

In a study of the association with eye color (227220) with
haplotype-tagging SNPs proximal to intron 1 of the OCA2 gene (611409)
that span the intergenic region and encompass the 3-prime end of the
upstream gene HERC2, Sturm et al. (2008) identified a SNP in intron 86
of HERC2, dbSNP rs12913832, that was strongly associated with eye color
in 3011 European individuals (P = 2 x 10(-78)). Individuals carrying the
CC genotype had only a 1% probability of having brown eyes, while those
with the TT genotype had an 80% probability. Haplotype analysis
combining the 3 SNPs in OCA2 identified by Duffy et al. (2007)
(611409.0013) with dbSNP rs12913832 followed by multiple ordinal
logistic regression showed that the HERC2 SNP alone was the best
predictor of eye color. Sturm et al. (2008) concluded that the conserved
region around dbSNP rs12913832 represents a regulatory region
controlling constitutive expression of OCA2, and that the C allele of
dbSNP rs12913832 leads to decreased expression of OCA2, particularly
within iris melanocytes, by abrogation of the binding site for HLTF
(603257) that regulates transcription of OCA2. Sturm et al. (2008) also
demonstrated that the OCA2 coding SNP R419Q (611409.0012) acts as a
penetrance modifier of dbSNP rs12913832.

In a 3-generation Danish family segregating blue and brown eye color,
Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate
region within the HERC2 gene. Further studies of SNPs within this region
among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs,
dbSNP rs1129038 and the strongly conserved dbSNP rs12913832, that showed
significant associations with the blue-eyed phenotype (p = 6.2 x
10(-46)). A common founder haplotype containing these SNPs was
identified among blue-eyed persons from Denmark, Turkey, and Jordan. In
vitro functional expression studies in human colon carcinoma cells
showed that what the authors referred to as the 'G' allele of dbSNP
rs12913832, present in blue-eyed individuals, had an inhibitory effect
on OCA2 promoter activity.

Visser et al. (2012) found that HLTF, LEF1 (153245), and MITF (156845)
bound to the enhancer region surrounding dbSNP rs12913832 in darkly
pigmented human melanocytes carrying the T allele of dbSNP rs12913832.
Binding was associated with long-range chromatin looping between the
enhancer and the OCA2 promoter, leading to elevated OCA2 expression. In
contrast, lightly pigmented melanocytes carrying the C allele of dbSNP
rs12913832 showed reduced enhancer binding, chromatin looping, and OCA2
expression.

.0004
MENTAL RETARDATION, AUTOSOMAL RECESSIVE 38
HERC2, PRO594LEU

In 7 patients of Amish or mixed Amish/Mennonite descent with autosomal
recessive mental retardation-38 (MRT38; 615516), Puffenberger et al.
(2012) identified a homozygous c.1781C-T transition in the HERC2 gene,
resulting in a pro594-to-leu (P594L) substitution at a highly conserved
residue in the first RLD1 domain. The mutation was found by a
combination of homozygosity mapping and exome sequencing. The mutation
was not present in the dbSNP database or in 760 alleles from Amish and
Mennonite controls. Cellular transfection studies demonstrated that the
mutant protein was less stable than wildtype and showed diffuse
cytosolic localization with the formation of abnormal aggregates.
Decreased abundance and/or activity of HERC2 could produce a toxic loss
of E3 ubiquitin ligase activity, leading to decreased degradation of ARC
(612461) and decreased postsynaptic glutamatergic AMPA receptor density.
Puffenberger et al. (2012) noted that this pathophysiologic mechanism is
similar to that thought to underlie Angelman syndrome (105830), which
results from loss of function of the UBE3A gene (601623) on chromosome
15q11. The affected individuals with the HERC2 mutation had global
developmental delay and autistic features similar to Angelman syndrome;
they also had blue irides.

*FIELD* RF
1. Bekker-Jensen, S.; Rendtlew Danielsen, J.; Fugger, K.; Gromova,
I.; Nerstedt, A.; Lukas, C.; Bartek, J.; Lukas, J.; Mailand, N.:
HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors
on damaged chromosomes. Nature Cell Biol. 12: 80-86, 2010. Note:
Erratum Nature Cell Biol. 12: 412 only, 2010.

2. Donnelly, M. P.; Paschou, P.; Grigorenko, E.; Gurwitz, D.; Barta,
C.; Lu, R.-B.; Zhukova, O. V.; Kim, J.-J.; Siniscalco, M.; New, M.;
Li, H.; Kajuna, S. L. B.; Manolopoulos, V. G.; Speed, W. C.; Pakstis,
A. J.; Kidd, J. R.; Kidd, K. K.: A global view of the OCA2-HERC2
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11. Sulem, P.; Gudbjartsson, D. F.; Stacey, S. N.; Helgason, A.; Rafnar,
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12. Visser, M.; Kayser, M.; Palstra, R.-J.: HERC2 rs12913832 modulates
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13. Wu, W.; Sato, K.; Koike, A.; Nishikawa, H.; Koizumi, H.; Venkitaraman,
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Res. 70: 6384-6392, 2010.

*FIELD* CN
Patricia A. Hartz - updated: 01/14/2014
Cassandra L. Kniffin - updated: 11/6/2013
Marla J. F. O'Neill - updated: 9/18/2012
Cassandra L. Kniffin - updated: 4/11/2008
Victor A. McKusick - updated: 3/31/2008
Anne M. Stumpf - updated: 1/16/2008

*FIELD* CD
Paul J. Converse: 4/11/2001

*FIELD* ED
mgross: 01/14/2014
carol: 11/7/2013
ckniffin: 11/6/2013
terry: 11/13/2012
alopez: 9/18/2012
carol: 2/11/2011
wwang: 4/18/2008
ckniffin: 4/11/2008
alopez: 4/11/2008
alopez: 4/3/2008
terry: 3/31/2008
alopez: 1/17/2008
alopez: 1/16/2008
carol: 9/12/2007
mgross: 4/11/2001