Full text data of UBE2A
UBE2A
(RAD6A)
[Confidence: low (only semi-automatic identification from reviews)]
Ubiquitin-conjugating enzyme E2 A; 6.3.2.19 (RAD6 homolog A; HR6A; hHR6A; Ubiquitin carrier protein A; Ubiquitin-protein ligase A)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ubiquitin-conjugating enzyme E2 A; 6.3.2.19 (RAD6 homolog A; HR6A; hHR6A; Ubiquitin carrier protein A; Ubiquitin-protein ligase A)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P49459
ID UBE2A_HUMAN Reviewed; 152 AA.
AC P49459; A6NFE9; A6NGR2; A6NMF5; B2R7R9; D3DWI1; Q4TTG1; Q96FX4;
read moreDT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 04-AUG-2003, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Ubiquitin-conjugating enzyme E2 A;
DE EC=6.3.2.19;
DE AltName: Full=RAD6 homolog A;
DE Short=HR6A;
DE Short=hHR6A;
DE AltName: Full=Ubiquitin carrier protein A;
DE AltName: Full=Ubiquitin-protein ligase A;
GN Name=UBE2A; Synonyms=RAD6A;
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] (ISOFORM 1).
RX PubMed=1717990; DOI=10.1073/pnas.88.20.8865;
RA Koken M.H.M., Reynolds P., Jaspers-Dekker I., Prakash L., Prakash S.,
RA Bootsma D., Hoeijmakers J.H.J.;
RT "Structural and functional conservation of two human homologs of the
RT yeast DNA repair gene RAD6.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8865-8869(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Subthalamic nucleus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION.
RX PubMed=16337599; DOI=10.1016/j.molcel.2005.11.012;
RA Kim J., Hake S.B., Roeder R.G.;
RT "The human homolog of yeast BRE1 functions as a transcriptional
RT coactivator through direct activator interactions.";
RL Mol. Cell 20:759-770(2005).
RN [8]
RP INVOLVEMENT IN MRXSN.
RX PubMed=16909393; DOI=10.1086/507047;
RA Nascimento R.M., Otto P.A., de Brouwer A.P., Vianna-Morgante A.M.;
RT "UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a
RT novel X-linked mental retardation syndrome.";
RL Am. J. Hum. Genet. 79:549-555(2006).
RN [9]
RP FUNCTION.
RX PubMed=20061386; DOI=10.1074/jbc.M109.089003;
RA David Y., Ziv T., Admon A., Navon A.;
RT "The E2 ubiquitin-conjugating enzymes direct polyubiquitination to
RT preferred lysines.";
RL J. Biol. Chem. 285:8595-8604(2010).
RN [10]
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 [11]
RP INTERACTION WITH WAC.
RX PubMed=21329877; DOI=10.1016/j.molcel.2011.01.024;
RA Zhang F., Yu X.;
RT "WAC, a functional partner of RNF20/40, regulates histone H2B
RT ubiquitination and gene transcription.";
RL Mol. Cell 41:384-397(2011).
RN [12]
RP PHOSPHORYLATION AT SER-120.
RX PubMed=22592529; DOI=10.4161/cc.20548;
RA Shchebet A., Karpiuk O., Kremmer E., Eick D., Johnsen S.A.;
RT "Phosphorylation by cyclin-dependent kinase-9 controls ubiquitin-
RT conjugating enzyme-2A function.";
RL Cell Cycle 11:2122-2127(2012).
RN [13]
RP VARIANTS MRXSN GLN-11 AND ARG-23.
RX PubMed=20412111; DOI=10.1111/j.1399-0004.2010.01429.x;
RA Budny B., Badura-Stronka M., Materna-Kiryluk A., Tzschach A.,
RA Raynaud M., Latos-Bielenska A., Ropers H.H.;
RT "Novel missense mutations in the ubiquitination-related gene UBE2A
RT cause a recognizable X-linked mental retardation syndrome.";
RL Clin. Genet. 77:541-551(2010).
CC -!- FUNCTION: Accepts ubiquitin from the E1 complex and catalyzes its
CC covalent attachment to other proteins. In association with the E3
CC enzyme BRE1 (RNF20 and/or RNF40), it plays a role in transcription
CC regulation by catalyzing the monoubiquitination of histone H2B at
CC 'Lys-120' to form H2BK120ub1. H2BK120ub1 gives a specific tag for
CC epigenetic transcriptional activation, elongation by RNA
CC polymerase II, telomeric silencing, and is also a prerequisite for
CC H3K4me and H3K79me formation. In vitro catalyzes 'Lys-11', as well
CC as 'Lys-48'-linked polyubiquitination. Required for
CC postreplication repair of UV-damaged DNA.
CC -!- CATALYTIC ACTIVITY: ATP + ubiquitin + protein lysine = AMP +
CC diphosphate + protein N-ubiquityllysine.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with RAD18 and WAC.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P49459-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P49459-2; Sequence=VSP_043852;
CC Name=3;
CC IsoId=P49459-3; Sequence=VSP_043851;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation at Ser-120 by CDK9 increases activity towards
CC histone H2B.
CC -!- DISEASE: Mental retardation, X-linked, syndromic, Nascimento-type
CC (MRXSN) [MIM:300860]: A disorder characterized by significantly
CC below average general intellectual functioning associated with
CC impairments in adaptive behavior and manifested during the
CC developmental period. MRXSN features include dysmorphic facies,
CC hirsutism, skin and nails abnormalities, obesity, speech anomalies
CC and seizures. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ubiquitin-conjugating enzyme family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ube2a/";
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DR EMBL; M74524; AAA35981.1; -; mRNA.
DR EMBL; AK297696; BAG60054.1; -; mRNA.
DR EMBL; AK313092; BAG35916.1; -; mRNA.
DR EMBL; DQ068065; AAY46159.1; -; Genomic_DNA.
DR EMBL; AC004913; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471161; EAW89861.1; -; Genomic_DNA.
DR EMBL; CH471161; EAW89862.1; -; Genomic_DNA.
DR EMBL; CH471161; EAW89863.1; -; Genomic_DNA.
DR EMBL; BC010175; AAH10175.1; -; mRNA.
DR PIR; A41222; A41222.
DR RefSeq; NP_001269090.1; NM_001282161.1.
DR RefSeq; NP_003327.2; NM_003336.3.
DR RefSeq; NP_861427.1; NM_181762.2.
DR UniGene; Hs.379466; -.
DR ProteinModelPortal; P49459; -.
DR SMR; P49459; 2-149.
DR DIP; DIP-24260N; -.
DR IntAct; P49459; 18.
DR MINT; MINT-267059; -.
DR STRING; 9606.ENSP00000360613; -.
DR PhosphoSite; P49459; -.
DR DMDM; 33518639; -.
DR PaxDb; P49459; -.
DR PRIDE; P49459; -.
DR DNASU; 7319; -.
DR Ensembl; ENST00000346330; ENSP00000335027; ENSG00000077721.
DR Ensembl; ENST00000371558; ENSP00000360613; ENSG00000077721.
DR Ensembl; ENST00000371569; ENSP00000360624; ENSG00000077721.
DR GeneID; 7319; -.
DR KEGG; hsa:7319; -.
DR UCSC; uc004erl.3; human.
DR CTD; 7319; -.
DR GeneCards; GC0XP118708; -.
DR HGNC; HGNC:12472; UBE2A.
DR MIM; 300860; phenotype.
DR MIM; 312180; gene.
DR neXtProt; NX_P49459; -.
DR Orphanet; 163956; Intellectual deficit, X-linked, Nascimento type.
DR PharmGKB; PA37122; -.
DR eggNOG; COG5078; -.
DR HOGENOM; HOG000233454; -.
DR HOVERGEN; HBG063308; -.
DR InParanoid; P49459; -.
DR KO; K10573; -.
DR OMA; PVPDNVM; -.
DR OrthoDB; EOG7M0NTH; -.
DR PhylomeDB; P49459; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P49459; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; UBE2A; human.
DR GeneWiki; UBE2A; -.
DR GenomeRNAi; 7319; -.
DR NextBio; 28614; -.
DR PRO; PR:P49459; -.
DR ArrayExpress; P49459; -.
DR Bgee; P49459; -.
DR CleanEx; HS_UBE2A; -.
DR Genevestigator; P49459; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0033503; C:HULC complex; IDA:UniProtKB.
DR GO; GO:0000790; C:nuclear chromatin; IEA:Ensembl.
DR GO; GO:0001741; C:XY body; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0002474; P:antigen processing and presentation of peptide antigen via MHC class I; TAS:Reactome.
DR GO; GO:0033522; P:histone H2A ubiquitination; IDA:UniProtKB.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0006301; P:postreplication repair; NAS:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB.
DR GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0009411; P:response to UV; IGI:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:UniProtKB.
DR Gene3D; 3.10.110.10; -; 1.
DR InterPro; IPR000608; UBQ-conjugat_E2.
DR InterPro; IPR023313; UBQ-conjugating_AS.
DR InterPro; IPR016135; UBQ-conjugating_enzyme/RWD.
DR Pfam; PF00179; UQ_con; 1.
DR SUPFAM; SSF54495; SSF54495; 1.
DR PROSITE; PS00183; UBIQUITIN_CONJUGAT_1; 1.
DR PROSITE; PS50127; UBIQUITIN_CONJUGAT_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Chromatin regulator;
KW Complete proteome; Disease mutation; DNA damage; DNA repair; Ligase;
KW Mental retardation; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Ubl conjugation pathway.
FT CHAIN 1 152 Ubiquitin-conjugating enzyme E2 A.
FT /FTId=PRO_0000082445.
FT ACT_SITE 88 88 Glycyl thioester intermediate (By
FT similarity).
FT MOD_RES 120 120 Phosphoserine; by CDK9.
FT VAR_SEQ 1 75 Missing (in isoform 3).
FT /FTId=VSP_043851.
FT VAR_SEQ 51 80 Missing (in isoform 2).
FT /FTId=VSP_043852.
FT VARIANT 11 11 R -> Q (in MRXSN).
FT /FTId=VAR_066627.
FT VARIANT 23 23 G -> R (in MRXSN).
FT /FTId=VAR_066628.
FT CONFLICT 49 49 E -> G (in Ref. 1; AAA35981).
SQ SEQUENCE 152 AA; 17315 MW; 0AAEB5B7770E47E2 CRC64;
MSTPARRRLM RDFKRLQEDP PAGVSGAPSE NNIMVWNAVI FGPEGTPFED GTFKLTIEFT
EEYPNKPPTV RFVSKMFHPN VYADGSICLD ILQNRWSPTY DVSSILTSIQ SLLDEPNPNS
PANSQAAQLY QENKREYEKR VSAIVEQSWR DC
//
ID UBE2A_HUMAN Reviewed; 152 AA.
AC P49459; A6NFE9; A6NGR2; A6NMF5; B2R7R9; D3DWI1; Q4TTG1; Q96FX4;
read moreDT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 04-AUG-2003, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Ubiquitin-conjugating enzyme E2 A;
DE EC=6.3.2.19;
DE AltName: Full=RAD6 homolog A;
DE Short=HR6A;
DE Short=hHR6A;
DE AltName: Full=Ubiquitin carrier protein A;
DE AltName: Full=Ubiquitin-protein ligase A;
GN Name=UBE2A; Synonyms=RAD6A;
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] (ISOFORM 1).
RX PubMed=1717990; DOI=10.1073/pnas.88.20.8865;
RA Koken M.H.M., Reynolds P., Jaspers-Dekker I., Prakash L., Prakash S.,
RA Bootsma D., Hoeijmakers J.H.J.;
RT "Structural and functional conservation of two human homologs of the
RT yeast DNA repair gene RAD6.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8865-8869(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Subthalamic nucleus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION.
RX PubMed=16337599; DOI=10.1016/j.molcel.2005.11.012;
RA Kim J., Hake S.B., Roeder R.G.;
RT "The human homolog of yeast BRE1 functions as a transcriptional
RT coactivator through direct activator interactions.";
RL Mol. Cell 20:759-770(2005).
RN [8]
RP INVOLVEMENT IN MRXSN.
RX PubMed=16909393; DOI=10.1086/507047;
RA Nascimento R.M., Otto P.A., de Brouwer A.P., Vianna-Morgante A.M.;
RT "UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a
RT novel X-linked mental retardation syndrome.";
RL Am. J. Hum. Genet. 79:549-555(2006).
RN [9]
RP FUNCTION.
RX PubMed=20061386; DOI=10.1074/jbc.M109.089003;
RA David Y., Ziv T., Admon A., Navon A.;
RT "The E2 ubiquitin-conjugating enzymes direct polyubiquitination to
RT preferred lysines.";
RL J. Biol. Chem. 285:8595-8604(2010).
RN [10]
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 [11]
RP INTERACTION WITH WAC.
RX PubMed=21329877; DOI=10.1016/j.molcel.2011.01.024;
RA Zhang F., Yu X.;
RT "WAC, a functional partner of RNF20/40, regulates histone H2B
RT ubiquitination and gene transcription.";
RL Mol. Cell 41:384-397(2011).
RN [12]
RP PHOSPHORYLATION AT SER-120.
RX PubMed=22592529; DOI=10.4161/cc.20548;
RA Shchebet A., Karpiuk O., Kremmer E., Eick D., Johnsen S.A.;
RT "Phosphorylation by cyclin-dependent kinase-9 controls ubiquitin-
RT conjugating enzyme-2A function.";
RL Cell Cycle 11:2122-2127(2012).
RN [13]
RP VARIANTS MRXSN GLN-11 AND ARG-23.
RX PubMed=20412111; DOI=10.1111/j.1399-0004.2010.01429.x;
RA Budny B., Badura-Stronka M., Materna-Kiryluk A., Tzschach A.,
RA Raynaud M., Latos-Bielenska A., Ropers H.H.;
RT "Novel missense mutations in the ubiquitination-related gene UBE2A
RT cause a recognizable X-linked mental retardation syndrome.";
RL Clin. Genet. 77:541-551(2010).
CC -!- FUNCTION: Accepts ubiquitin from the E1 complex and catalyzes its
CC covalent attachment to other proteins. In association with the E3
CC enzyme BRE1 (RNF20 and/or RNF40), it plays a role in transcription
CC regulation by catalyzing the monoubiquitination of histone H2B at
CC 'Lys-120' to form H2BK120ub1. H2BK120ub1 gives a specific tag for
CC epigenetic transcriptional activation, elongation by RNA
CC polymerase II, telomeric silencing, and is also a prerequisite for
CC H3K4me and H3K79me formation. In vitro catalyzes 'Lys-11', as well
CC as 'Lys-48'-linked polyubiquitination. Required for
CC postreplication repair of UV-damaged DNA.
CC -!- CATALYTIC ACTIVITY: ATP + ubiquitin + protein lysine = AMP +
CC diphosphate + protein N-ubiquityllysine.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with RAD18 and WAC.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P49459-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P49459-2; Sequence=VSP_043852;
CC Name=3;
CC IsoId=P49459-3; Sequence=VSP_043851;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation at Ser-120 by CDK9 increases activity towards
CC histone H2B.
CC -!- DISEASE: Mental retardation, X-linked, syndromic, Nascimento-type
CC (MRXSN) [MIM:300860]: A disorder characterized by significantly
CC below average general intellectual functioning associated with
CC impairments in adaptive behavior and manifested during the
CC developmental period. MRXSN features include dysmorphic facies,
CC hirsutism, skin and nails abnormalities, obesity, speech anomalies
CC and seizures. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ubiquitin-conjugating enzyme family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ube2a/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M74524; AAA35981.1; -; mRNA.
DR EMBL; AK297696; BAG60054.1; -; mRNA.
DR EMBL; AK313092; BAG35916.1; -; mRNA.
DR EMBL; DQ068065; AAY46159.1; -; Genomic_DNA.
DR EMBL; AC004913; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471161; EAW89861.1; -; Genomic_DNA.
DR EMBL; CH471161; EAW89862.1; -; Genomic_DNA.
DR EMBL; CH471161; EAW89863.1; -; Genomic_DNA.
DR EMBL; BC010175; AAH10175.1; -; mRNA.
DR PIR; A41222; A41222.
DR RefSeq; NP_001269090.1; NM_001282161.1.
DR RefSeq; NP_003327.2; NM_003336.3.
DR RefSeq; NP_861427.1; NM_181762.2.
DR UniGene; Hs.379466; -.
DR ProteinModelPortal; P49459; -.
DR SMR; P49459; 2-149.
DR DIP; DIP-24260N; -.
DR IntAct; P49459; 18.
DR MINT; MINT-267059; -.
DR STRING; 9606.ENSP00000360613; -.
DR PhosphoSite; P49459; -.
DR DMDM; 33518639; -.
DR PaxDb; P49459; -.
DR PRIDE; P49459; -.
DR DNASU; 7319; -.
DR Ensembl; ENST00000346330; ENSP00000335027; ENSG00000077721.
DR Ensembl; ENST00000371558; ENSP00000360613; ENSG00000077721.
DR Ensembl; ENST00000371569; ENSP00000360624; ENSG00000077721.
DR GeneID; 7319; -.
DR KEGG; hsa:7319; -.
DR UCSC; uc004erl.3; human.
DR CTD; 7319; -.
DR GeneCards; GC0XP118708; -.
DR HGNC; HGNC:12472; UBE2A.
DR MIM; 300860; phenotype.
DR MIM; 312180; gene.
DR neXtProt; NX_P49459; -.
DR Orphanet; 163956; Intellectual deficit, X-linked, Nascimento type.
DR PharmGKB; PA37122; -.
DR eggNOG; COG5078; -.
DR HOGENOM; HOG000233454; -.
DR HOVERGEN; HBG063308; -.
DR InParanoid; P49459; -.
DR KO; K10573; -.
DR OMA; PVPDNVM; -.
DR OrthoDB; EOG7M0NTH; -.
DR PhylomeDB; P49459; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P49459; -.
DR UniPathway; UPA00143; -.
DR ChiTaRS; UBE2A; human.
DR GeneWiki; UBE2A; -.
DR GenomeRNAi; 7319; -.
DR NextBio; 28614; -.
DR PRO; PR:P49459; -.
DR ArrayExpress; P49459; -.
DR Bgee; P49459; -.
DR CleanEx; HS_UBE2A; -.
DR Genevestigator; P49459; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0033503; C:HULC complex; IDA:UniProtKB.
DR GO; GO:0000790; C:nuclear chromatin; IEA:Ensembl.
DR GO; GO:0001741; C:XY body; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0002474; P:antigen processing and presentation of peptide antigen via MHC class I; TAS:Reactome.
DR GO; GO:0033522; P:histone H2A ubiquitination; IDA:UniProtKB.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0006301; P:postreplication repair; NAS:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IDA:UniProtKB.
DR GO; GO:0070979; P:protein K11-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0009411; P:response to UV; IGI:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; NAS:UniProtKB.
DR Gene3D; 3.10.110.10; -; 1.
DR InterPro; IPR000608; UBQ-conjugat_E2.
DR InterPro; IPR023313; UBQ-conjugating_AS.
DR InterPro; IPR016135; UBQ-conjugating_enzyme/RWD.
DR Pfam; PF00179; UQ_con; 1.
DR SUPFAM; SSF54495; SSF54495; 1.
DR PROSITE; PS00183; UBIQUITIN_CONJUGAT_1; 1.
DR PROSITE; PS50127; UBIQUITIN_CONJUGAT_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Chromatin regulator;
KW Complete proteome; Disease mutation; DNA damage; DNA repair; Ligase;
KW Mental retardation; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Ubl conjugation pathway.
FT CHAIN 1 152 Ubiquitin-conjugating enzyme E2 A.
FT /FTId=PRO_0000082445.
FT ACT_SITE 88 88 Glycyl thioester intermediate (By
FT similarity).
FT MOD_RES 120 120 Phosphoserine; by CDK9.
FT VAR_SEQ 1 75 Missing (in isoform 3).
FT /FTId=VSP_043851.
FT VAR_SEQ 51 80 Missing (in isoform 2).
FT /FTId=VSP_043852.
FT VARIANT 11 11 R -> Q (in MRXSN).
FT /FTId=VAR_066627.
FT VARIANT 23 23 G -> R (in MRXSN).
FT /FTId=VAR_066628.
FT CONFLICT 49 49 E -> G (in Ref. 1; AAA35981).
SQ SEQUENCE 152 AA; 17315 MW; 0AAEB5B7770E47E2 CRC64;
MSTPARRRLM RDFKRLQEDP PAGVSGAPSE NNIMVWNAVI FGPEGTPFED GTFKLTIEFT
EEYPNKPPTV RFVSKMFHPN VYADGSICLD ILQNRWSPTY DVSSILTSIQ SLLDEPNPNS
PANSQAAQLY QENKREYEKR VSAIVEQSWR DC
//
MIM
300860
*RECORD*
*FIELD* NO
300860
*FIELD* TI
#300860 MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE; MRXSN
;;MENTAL RETARDATION, X-LINKED, SYNDROMIC 30; MRXS30
read more*FIELD* TX
A number sign (#) is used with this entry because the Nascimento form of
syndromic X-linked mental retardation (MRXSN) is caused by mutation in
the UBE2A gene (312180) on chromosome Xq24-q25.
DESCRIPTION
The Nascimento type of X-linked syndromic mental retardation is
characterized by dysmorphic features, including large head, synophrys,
prominent supraorbital ridges, almond-shaped and deep-set eyes, large
ears, wide mouth, myxedematous appearance, hirsutism, abnormal hair
whorls, micropenis, and onychodystrophy. Female carriers have normal
cognition, but may show subtle facial features (summary by Budny et al.,
2010).
CLINICAL FEATURES
Nascimento et al. (2006) reported a family with 3 mentally retarded
males in 2 generations, related through their clinically normal mothers.
The patients were 46, 19, and 5 years of age, respectively. Dysmorphic
features included synophrys, upslanted palpebral fissures, large mouth
with downturned corners and thin lips, short, broad neck, low posterior
hairline, and hair whorls; 2 had midface hypoplasia and a wide face. The
2 older men had a large head circumference. All were heavy-set with
marked generalized hirsutism and a myxedematous appearance. Other
features included widely spaced nipples, small penis, small, flat feet,
dry skin, and onychodystrophy. All had seizures, 2 had absent speech,
and imaging of 2 patients showed white matter hypodensities. The oldest
patient developed acute myeloid leukemia at age 46 years.
Budny et al. (2010) reported a 5-generation family in which 5 males had
a syndromic form of X-linked mental retardation. The patients had
similar physical features, with a large head, prominent supraorbital
ridges, synophrys, deep-set, almond-shaped eyes, large ears, wide mouth,
widely spaced nipples, and large great toes. Two had hypopigmented skin
spots and 2 had onychodystrophy. Two males from another family had a
similar disorder. Other common features in these patients included
hirsutism, abnormal hair whorls, low posterior hairline, short neck, and
micropenis. All were mentally retarded with very poor speech, and most
had seizures, aggressive behavior, and echolalia. The phenotype was
remarkably similar to that described by Nascimento et al. (2006).
MOLECULAR GENETICS
In 3 males with X-linked syndromic mental retardation, Nascimento et al.
(2006) identified a nonsense mutation in the UBE2A gene (Q128X;
312180.0001). The mutation was found after screening of candidate genes
within a shared region on chromosome Xq23-q25 identified by genotyping
of 36 markers spaced approximately 5 cM apart. The presumptive obligate
carriers had completely skewed X inactivation in leukocytes. The sister
of 1 of the affected males, with a rather random X-inactivation, did not
carry this mutation. No mutations in UBE2A were found in 19 idiopathic
XLMR-affected families mapped to intervals encompassing UBE2A.
In affected members of 2 unrelated families with syndromic XLMR, Budny
et al. (2010) identified 2 different missense mutations in the UBE2A
gene (312180.0002 and 312180.0003, respectively).
CYTOGENETICS
De Leeuw et al. (2010) reported 3 unrelated boys with mental
retardation, severely impaired speech, hypotonia, and similar dysmorphic
facial features, including synophrys, hypertelorism, and depressed nasal
bridge. Two had congenital cataracts and 2 had a short neck. All had
ventricular septal defects, which closed spontaneously in 2 patients.
Two had a small penis, 2 had cryptorchidism, 2 had hypospadias, and 1
had duplicated kidneys. All had seizures, 1 had white matter lesions on
brain MRI, and 1 had cerebellar hypoplasia. Genomewide array analysis
identified deletions of Xq24 ranging from 240 to 360 kb, which were
different in each patient. All deletions were inherited from an
unaffected mother, and each mother showed skewed X inactivation. The
deletions encompassed at least 5 genes, including UBE2A and SLC25A5
(300150). Since the clinical features resembled those in patients with
point mutations in the UBE2A gene, de Leeuw et al. (2010) concluded that
loss of UBE2A is sufficient to account for most of the features in these
patients, but also suggested that the cardiac septal defects may be due
to loss of SLC25A5.
*FIELD* RF
1. Budny, B.; Badura-Stronka, M.; Materna-Kiryluk, A.; Tzschach, A.;
Raynaud, M.; Latos-Bielenska, A.; Ropers, H. H.: Novel missense mutations
in the ubiquitination-related gene UBE2A cause a recognizable X-linked
mental retardation syndrome. Clin. Genet. 77: 541-551, 2010.
2. de Leeuw, N.; Bulk, S.; Green, A.; Jaeckle-Santos, L.; Baker, L.
A.; Zinn, A. R.; Kleefstra, T.; van der Smagt, J. J.; Vianne Morgante,
A. M.; de Vries, B. B. A.; van Bokhoven, H.; de Brouwer, A. P. M.
: UBE2A deficiency syndrome: mild to severe intellectual disability
accompanied by seizures, absent speech, urogenital, and skin anomalies
in male patients. Am. J. Med. Genet. 152A: 3084-3090, 2010.
3. Nascimento, R. M. P.; Otto, P. A.; de Brouwer, A. P. M.; Vianna-Morgante,
A. M.: UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated
in a novel X-linked mental retardation syndrome. Am. J. Hum. Genet. 79:
549-555, 2006.
*FIELD* CS
INHERITANCE:
X-linked recessive
GROWTH:
[Weight];
Increased weight
HEAD AND NECK:
[Head];
Large head;
[Face];
Midface hypoplasia;
Wide face;
Prominent supraorbital ridges;
[Eyes];
Synophrys;
Upslanting palpebral fissures;
Deep-set eyes;
Almond-shaped eyes;
[Nose];
Low nasal bridge;
[Mouth];
Large mouth;
Downturned corners of the mouth;
Thin lips;
[Neck];
Short, broad neck
CHEST:
[Breasts];
Widely spaced nipples
GENITOURINARY:
[External genitalia, male];
Small penis
SKELETAL:
[Feet];
Flat feet;
Small feet;
Broad first toe
SKIN, NAILS, HAIR:
[Skin];
Dry skin;
Hypopigmented spots (less common);
[Nails];
Onychodystrophy;
[Hair];
Hirsutism, generalized;
Low posterior hairline;
Synophrys;
Hair whorls
MUSCLE, SOFT TISSUE:
Myxedematous appearance
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Lack of speech or poor speech;
White matter hypodensities on brain imaging;
[Behavioral/psychiatric manifestations];
Echolalia;
Aggression
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-conjugating enzyme E2A gene (UBE2A,
312180.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 2/8/2012
*FIELD* CD
Cassandra L. Kniffin: 10/25/2011
*FIELD* ED
joanna: 04/06/2012
joanna: 2/28/2012
ckniffin: 2/8/2012
joanna: 12/5/2011
ckniffin: 10/25/2011
*FIELD* CN
Cassandra L. Kniffin - updated: 12/20/2011
*FIELD* CD
Cassandra L. Kniffin: 10/25/2011
*FIELD* ED
carol: 11/26/2012
carol: 12/22/2011
ckniffin: 12/20/2011
carol: 10/26/2011
ckniffin: 10/25/2011
*RECORD*
*FIELD* NO
300860
*FIELD* TI
#300860 MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE; MRXSN
;;MENTAL RETARDATION, X-LINKED, SYNDROMIC 30; MRXS30
read more*FIELD* TX
A number sign (#) is used with this entry because the Nascimento form of
syndromic X-linked mental retardation (MRXSN) is caused by mutation in
the UBE2A gene (312180) on chromosome Xq24-q25.
DESCRIPTION
The Nascimento type of X-linked syndromic mental retardation is
characterized by dysmorphic features, including large head, synophrys,
prominent supraorbital ridges, almond-shaped and deep-set eyes, large
ears, wide mouth, myxedematous appearance, hirsutism, abnormal hair
whorls, micropenis, and onychodystrophy. Female carriers have normal
cognition, but may show subtle facial features (summary by Budny et al.,
2010).
CLINICAL FEATURES
Nascimento et al. (2006) reported a family with 3 mentally retarded
males in 2 generations, related through their clinically normal mothers.
The patients were 46, 19, and 5 years of age, respectively. Dysmorphic
features included synophrys, upslanted palpebral fissures, large mouth
with downturned corners and thin lips, short, broad neck, low posterior
hairline, and hair whorls; 2 had midface hypoplasia and a wide face. The
2 older men had a large head circumference. All were heavy-set with
marked generalized hirsutism and a myxedematous appearance. Other
features included widely spaced nipples, small penis, small, flat feet,
dry skin, and onychodystrophy. All had seizures, 2 had absent speech,
and imaging of 2 patients showed white matter hypodensities. The oldest
patient developed acute myeloid leukemia at age 46 years.
Budny et al. (2010) reported a 5-generation family in which 5 males had
a syndromic form of X-linked mental retardation. The patients had
similar physical features, with a large head, prominent supraorbital
ridges, synophrys, deep-set, almond-shaped eyes, large ears, wide mouth,
widely spaced nipples, and large great toes. Two had hypopigmented skin
spots and 2 had onychodystrophy. Two males from another family had a
similar disorder. Other common features in these patients included
hirsutism, abnormal hair whorls, low posterior hairline, short neck, and
micropenis. All were mentally retarded with very poor speech, and most
had seizures, aggressive behavior, and echolalia. The phenotype was
remarkably similar to that described by Nascimento et al. (2006).
MOLECULAR GENETICS
In 3 males with X-linked syndromic mental retardation, Nascimento et al.
(2006) identified a nonsense mutation in the UBE2A gene (Q128X;
312180.0001). The mutation was found after screening of candidate genes
within a shared region on chromosome Xq23-q25 identified by genotyping
of 36 markers spaced approximately 5 cM apart. The presumptive obligate
carriers had completely skewed X inactivation in leukocytes. The sister
of 1 of the affected males, with a rather random X-inactivation, did not
carry this mutation. No mutations in UBE2A were found in 19 idiopathic
XLMR-affected families mapped to intervals encompassing UBE2A.
In affected members of 2 unrelated families with syndromic XLMR, Budny
et al. (2010) identified 2 different missense mutations in the UBE2A
gene (312180.0002 and 312180.0003, respectively).
CYTOGENETICS
De Leeuw et al. (2010) reported 3 unrelated boys with mental
retardation, severely impaired speech, hypotonia, and similar dysmorphic
facial features, including synophrys, hypertelorism, and depressed nasal
bridge. Two had congenital cataracts and 2 had a short neck. All had
ventricular septal defects, which closed spontaneously in 2 patients.
Two had a small penis, 2 had cryptorchidism, 2 had hypospadias, and 1
had duplicated kidneys. All had seizures, 1 had white matter lesions on
brain MRI, and 1 had cerebellar hypoplasia. Genomewide array analysis
identified deletions of Xq24 ranging from 240 to 360 kb, which were
different in each patient. All deletions were inherited from an
unaffected mother, and each mother showed skewed X inactivation. The
deletions encompassed at least 5 genes, including UBE2A and SLC25A5
(300150). Since the clinical features resembled those in patients with
point mutations in the UBE2A gene, de Leeuw et al. (2010) concluded that
loss of UBE2A is sufficient to account for most of the features in these
patients, but also suggested that the cardiac septal defects may be due
to loss of SLC25A5.
*FIELD* RF
1. Budny, B.; Badura-Stronka, M.; Materna-Kiryluk, A.; Tzschach, A.;
Raynaud, M.; Latos-Bielenska, A.; Ropers, H. H.: Novel missense mutations
in the ubiquitination-related gene UBE2A cause a recognizable X-linked
mental retardation syndrome. Clin. Genet. 77: 541-551, 2010.
2. de Leeuw, N.; Bulk, S.; Green, A.; Jaeckle-Santos, L.; Baker, L.
A.; Zinn, A. R.; Kleefstra, T.; van der Smagt, J. J.; Vianne Morgante,
A. M.; de Vries, B. B. A.; van Bokhoven, H.; de Brouwer, A. P. M.
: UBE2A deficiency syndrome: mild to severe intellectual disability
accompanied by seizures, absent speech, urogenital, and skin anomalies
in male patients. Am. J. Med. Genet. 152A: 3084-3090, 2010.
3. Nascimento, R. M. P.; Otto, P. A.; de Brouwer, A. P. M.; Vianna-Morgante,
A. M.: UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated
in a novel X-linked mental retardation syndrome. Am. J. Hum. Genet. 79:
549-555, 2006.
*FIELD* CS
INHERITANCE:
X-linked recessive
GROWTH:
[Weight];
Increased weight
HEAD AND NECK:
[Head];
Large head;
[Face];
Midface hypoplasia;
Wide face;
Prominent supraorbital ridges;
[Eyes];
Synophrys;
Upslanting palpebral fissures;
Deep-set eyes;
Almond-shaped eyes;
[Nose];
Low nasal bridge;
[Mouth];
Large mouth;
Downturned corners of the mouth;
Thin lips;
[Neck];
Short, broad neck
CHEST:
[Breasts];
Widely spaced nipples
GENITOURINARY:
[External genitalia, male];
Small penis
SKELETAL:
[Feet];
Flat feet;
Small feet;
Broad first toe
SKIN, NAILS, HAIR:
[Skin];
Dry skin;
Hypopigmented spots (less common);
[Nails];
Onychodystrophy;
[Hair];
Hirsutism, generalized;
Low posterior hairline;
Synophrys;
Hair whorls
MUSCLE, SOFT TISSUE:
Myxedematous appearance
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Lack of speech or poor speech;
White matter hypodensities on brain imaging;
[Behavioral/psychiatric manifestations];
Echolalia;
Aggression
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-conjugating enzyme E2A gene (UBE2A,
312180.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 2/8/2012
*FIELD* CD
Cassandra L. Kniffin: 10/25/2011
*FIELD* ED
joanna: 04/06/2012
joanna: 2/28/2012
ckniffin: 2/8/2012
joanna: 12/5/2011
ckniffin: 10/25/2011
*FIELD* CN
Cassandra L. Kniffin - updated: 12/20/2011
*FIELD* CD
Cassandra L. Kniffin: 10/25/2011
*FIELD* ED
carol: 11/26/2012
carol: 12/22/2011
ckniffin: 12/20/2011
carol: 10/26/2011
ckniffin: 10/25/2011
MIM
312180
*RECORD*
*FIELD* NO
312180
*FIELD* TI
*312180 UBIQUITIN-CONJUGATING ENZYME E2A; UBE2A
;;RAD6, YEAST, HOMOLOG OF, TYPE A; RAD6A;;
read moreHHR6A
*FIELD* TX
CLONING
As deduced from the pleiotropic phenotype of rad6 deletion mutants in
Saccharomyces cerevisiae, the RAD6 protein plays an important role in
various cellular processes. The protein is strongly conserved in
eukaryotic evolution, a property that permitted Koken et al. (1991) to
clone to human homologs by evolutionary walking using
Schizosaccharomyces pombe and Drosophila melanogaster homologs as
'intermediates.' The human HHR6A and HHR6B (179095) proteins (HHR for
human homolog of rad6) shared about 95% amino acid sequence identity
with each other and about 70% amino acid sequence with their yeast
counterparts, but notably lacked the acidic C-terminal domain, the
occurrence of which seemed to be limited to S. cerevisiae rad6.
GENE FUNCTION
Ulrich and Jentsch (2000) demonstrated that RAD18 (605256) and RAD5
(608048), play a central role in mediating physical contacts between the
members of the RAD6 pathway. RAD5 recruits the UBC13 (603679)-MMS2
(603001) complex to DNA by means of its RING finger domain. Moreover,
RAD5 association with RAD18 brings UBC13-MMS2 into contact with the
RAD6-RAD18 complex. Interaction between the 2 RING finger proteins thus
promotes the formation of a heteromeric complex in which the 2 distinct
ubiquitin-conjugating activities of RAD6 and UBC13-MMS2 can be closely
coordinated. Ulrich and Jentsch (2000) found that while UBC13 and MMS2
are largely cytosolic proteins, DNA damage triggers their redistribution
to the nucleus.
Hishida et al. (2009) examined the response of yeast cells to chronic
low dose ultraviolet light (CLUV) and identified a key role for the
RAD6-RAD18-RAD5 error-free postreplication repair (PRR) pathway in
promoting cell growth and survival. They found that loss of the RAD6
error-free PRR pathway resulted in DNA damage checkpoint-induced G2
arrest in CLUV-exposed cells, whereas wildtype and nucleotide excision
repair-deficient cells were largely unaffected. Cell cycle arrest in the
absence of the RAD6 error-free PRR pathway was not caused by a repair
defect or by the accumulation of ultraviolet-induced photoproducts.
Hishida et al. (2009) observed increased replication protein A (RPA; see
179835)- and Rad52 (600392)-yellow fluorescent protein foci in the
CLUV-exposed Rad18 (605256)-delta cells and demonstrated that
Rad52-mediated homologous recombination is required for the viability of
the Rad18-delta cells after release from CLUV-induced G2 arrest. These
and other data presented suggest that, in response to environmental
levels of ultraviolet exposure, the RAD6 error-free PRR pathway promotes
replication of damaged templates without the generation of extensive
single-stranded DNA regions. Thus this pathway is specifically important
during chronic low dose ultraviolet exposure to prevent
counterproductive DNA checkpoint activation and allow cells to
proliferate normally.
MAPPING
By in situ hybridization with biotinylated probes, Koken et al. (1992)
localized the RAD6A gene to Xq24-q25 and the RAD6B gene (179095) to
5q23-q31. The assignment of RAD6A to the X chromosome was confirmed with
an X-specific human-mouse/hamster somatic cell hybrid panel.
MOLECULAR GENETICS
In 3 males with X-linked syndromic mental retardation (MRXSN; 300860),
Nascimento et al. (2006) identified a nonsense mutation in the UBE2A
gene (Q128X; 312180.0001). The presumptive obligate carriers had
completely skewed X inactivation in leukocytes, as demonstrated by the
methylation status of the CAG repeat of the androgen receptor gene
(313700). Indeed, skewed X-chromosome inactivation appears to be
characteristic of carriers of many gene mutations involved in XLMR
(Plenge et al., 2002). This prompted a search for an X-linked gene
involved in the syndrome in this family. Given the family's small size,
an inclusion-mapping strategy was performed. Genotyping of 36 markers
spaced at approximately 5 cM disclosed 3 loci, at Xq23-q25, harboring
alleles shared by all 3 affected males. Nascimento et al. (2006) found
30 genes within a narrowed candidate region that were expressed in
brain. However, only 1 of these gene, UBE2A, was expressed in both brain
and lymphocytes. Because of the skewed X-inactivation in the patients'
mothers, which likely represented the survival/proliferation advantage
of lymphocytes with the active normal allele in a woman with the
mutation, the authors sequenced the UBE2A gene and found a 382C-T
substitution leading to a premature stop codon (Q128X; 312180) in all 3
affected males and in their mothers. The sister of 1 of the affected
males, with a rather random X-inactivation pattern as documented by the
methylation status of the AR gene, did not carry this mutation. No
mutations in UBE2A were found in 19 idiopathic XLMR-affected families
mapped to intervals encompassing UBE2A.
In affected members of 2 unrelated families with syndromic XLMR, Budny
et al. (2010) identified 2 different missense mutations in the UBE2A
gene (312180.0002 and 312180.0003, respectively). The phenotype was
characterized by mental retardation and very poor speech, as well as
striking dysmorphic features, including large head, synophrys, prominent
supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide
mouth, myxedematous appearance, hirsutism, abnormal hair whorls,
micropenis, and onychodystrophy.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE
UBE2A, GLN128TER
In 3 males with an X-linked mental retardation syndrome (300860) in 3
sibships connected through carrier females in 2 generations, Nascimento
et al. (2006) identified a 382C-T transition in the UBE2A gene leading
to a premature UAG stop codon (gln128 to stop; Q128X). As a consequence
of the mutation, the predicted polypeptide lacked the 25 C-terminal
amino acid residues. The importance of this terminal sequence for UBE2
function was inferred by its conservation in vertebrates and in
Drosophila. No UBE2A mutations were found in 15 families with
nonsyndromic and 4 families with syndromic idiopathic XLMR previously
mapped to intervals encompassing this gene. This was the first
description of a mutation in a ubiquitin-conjugating enzyme gene as the
cause of a human disease. The affected males in the family presented a
neurodevelopmental disorder that included seizures, severe speech
impairment, marked general hirsutism, synophrys, and a low posterior
hairline.
.0002
MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE
UBE2A, GLY23ARG
In affected members of a large 5-generation family with X-linked
syndromic mental retardation (300860), Budny et al. (2010) identified a
67G-A transition in exon 2 of the UBE2A gene, resulting in a
gly23-to-arg (G23R) substitution in a highly conserved residue. The
mutation was not found in unaffected family members or in 168 male
controls. Three obligate female carriers showed skewed X-inactivation
profiles. The mutation was found by linkage analysis followed by
candidate gene sequencing. Functional studies were not performed.
.0003
MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE
UBE2A, ARG11GLN
In 2 males from a family with X-linked syndromic mental retardation
(300860), Budny et al. (2010) identified a 32G-A transition in exon 1 of
the UBE2A gene, resulting in an arg11-to-gln (R11Q) substitution in a
highly conserved residue. The mutation was not found in unaffected
family members or in 168 male controls. Functional studies were not
performed.
*FIELD* RF
1. Budny, B.; Badura-Stronka, M.; Materna-Kiryluk, A.; Tzschach, A.;
Raynaud, M.; Latos-Bielenska, A.; Ropers, H. H.: Novel missense mutations
in the ubiquitination-related gene UBE2A cause a recognizable X-linked
mental retardation syndrome. Clin. Genet. 77: 541-551, 2010.
2. Hishida, T.; Kubota, Y.; Carr, A. M.; Iwasaki, H.: RAD6-RAD18-RAD5-pathway-dependent
tolerance to chronic low-dose ultraviolet light. Nature 457: 612-615,
2009.
3. Koken, M. H. M.; Reynolds, P.; Jaspers-Dekker, I.; Prakash, L.;
Prakash, S.; Bootsma, D.; Hoeijmakers, J. H. J.: Structural and functional
conservation of two human homologs of the yeast DNA repair gene RAD6. Proc.
Nat. Acad. Sci. 88: 8865-8869, 1991.
4. Koken, M. H. M.; Smit, E. M. E.; Jaspers-Dekker, I.; Oostra, B.
A.; Hagemeijer, A.; Bootsma, D.; Hoeijmakers, J. H. J.: Localization
of two human homologs, HHR6A and HHR6B, of the yeast DNA repair gene
RAD6 to chromosomes Xq24-q25 and 5q23-q31. Genomics 12: 447-453,
1992.
5. Nascimento, R. M. P.; Otto, P. A.; de Brouwer, A. P. M.; Vianna-Morgante,
A. M.: UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated
in a novel X-linked mental retardation syndrome. Am. J. Hum. Genet. 79:
549-555, 2006.
6. Plenge, R. M.; Stevenson, R. A.; Lubs, H. A.; Schwartz, C. E.;
Willard, H. F.: Skewed X-chromosome inactivation is a common feature
of X-linked mental retardation disorders. Am. J. Hum. Genet. 71:
168-173, 2002.
7. Ulrich, H. D.; Jentsch, S.: Two RING finger proteins mediate cooperation
between ubiquitin-conjugating enzymes in DNA repair. EMBO J. 19:
3388-3397, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/20/2011
Ada Hamosh - updated: 2/13/2009
Victor A. McKusick - updated: 8/23/2006
Ada Hamosh - updated: 11/21/2002
*FIELD* CD
Victor A. McKusick: 2/21/1992
*FIELD* ED
carol: 04/06/2012
carol: 12/22/2011
ckniffin: 12/20/2011
carol: 10/28/2011
carol: 10/26/2011
ckniffin: 10/25/2011
carol: 10/25/2011
alopez: 2/16/2009
terry: 2/13/2009
alopez: 1/29/2007
alopez: 8/28/2006
terry: 8/23/2006
alopez: 11/21/2002
terry: 11/18/2002
alopez: 3/4/1999
mark: 2/20/1997
mark: 10/26/1996
mark: 9/12/1995
carol: 3/17/1994
mimadm: 2/28/1994
supermim: 3/17/1992
carol: 3/2/1992
*RECORD*
*FIELD* NO
312180
*FIELD* TI
*312180 UBIQUITIN-CONJUGATING ENZYME E2A; UBE2A
;;RAD6, YEAST, HOMOLOG OF, TYPE A; RAD6A;;
read moreHHR6A
*FIELD* TX
CLONING
As deduced from the pleiotropic phenotype of rad6 deletion mutants in
Saccharomyces cerevisiae, the RAD6 protein plays an important role in
various cellular processes. The protein is strongly conserved in
eukaryotic evolution, a property that permitted Koken et al. (1991) to
clone to human homologs by evolutionary walking using
Schizosaccharomyces pombe and Drosophila melanogaster homologs as
'intermediates.' The human HHR6A and HHR6B (179095) proteins (HHR for
human homolog of rad6) shared about 95% amino acid sequence identity
with each other and about 70% amino acid sequence with their yeast
counterparts, but notably lacked the acidic C-terminal domain, the
occurrence of which seemed to be limited to S. cerevisiae rad6.
GENE FUNCTION
Ulrich and Jentsch (2000) demonstrated that RAD18 (605256) and RAD5
(608048), play a central role in mediating physical contacts between the
members of the RAD6 pathway. RAD5 recruits the UBC13 (603679)-MMS2
(603001) complex to DNA by means of its RING finger domain. Moreover,
RAD5 association with RAD18 brings UBC13-MMS2 into contact with the
RAD6-RAD18 complex. Interaction between the 2 RING finger proteins thus
promotes the formation of a heteromeric complex in which the 2 distinct
ubiquitin-conjugating activities of RAD6 and UBC13-MMS2 can be closely
coordinated. Ulrich and Jentsch (2000) found that while UBC13 and MMS2
are largely cytosolic proteins, DNA damage triggers their redistribution
to the nucleus.
Hishida et al. (2009) examined the response of yeast cells to chronic
low dose ultraviolet light (CLUV) and identified a key role for the
RAD6-RAD18-RAD5 error-free postreplication repair (PRR) pathway in
promoting cell growth and survival. They found that loss of the RAD6
error-free PRR pathway resulted in DNA damage checkpoint-induced G2
arrest in CLUV-exposed cells, whereas wildtype and nucleotide excision
repair-deficient cells were largely unaffected. Cell cycle arrest in the
absence of the RAD6 error-free PRR pathway was not caused by a repair
defect or by the accumulation of ultraviolet-induced photoproducts.
Hishida et al. (2009) observed increased replication protein A (RPA; see
179835)- and Rad52 (600392)-yellow fluorescent protein foci in the
CLUV-exposed Rad18 (605256)-delta cells and demonstrated that
Rad52-mediated homologous recombination is required for the viability of
the Rad18-delta cells after release from CLUV-induced G2 arrest. These
and other data presented suggest that, in response to environmental
levels of ultraviolet exposure, the RAD6 error-free PRR pathway promotes
replication of damaged templates without the generation of extensive
single-stranded DNA regions. Thus this pathway is specifically important
during chronic low dose ultraviolet exposure to prevent
counterproductive DNA checkpoint activation and allow cells to
proliferate normally.
MAPPING
By in situ hybridization with biotinylated probes, Koken et al. (1992)
localized the RAD6A gene to Xq24-q25 and the RAD6B gene (179095) to
5q23-q31. The assignment of RAD6A to the X chromosome was confirmed with
an X-specific human-mouse/hamster somatic cell hybrid panel.
MOLECULAR GENETICS
In 3 males with X-linked syndromic mental retardation (MRXSN; 300860),
Nascimento et al. (2006) identified a nonsense mutation in the UBE2A
gene (Q128X; 312180.0001). The presumptive obligate carriers had
completely skewed X inactivation in leukocytes, as demonstrated by the
methylation status of the CAG repeat of the androgen receptor gene
(313700). Indeed, skewed X-chromosome inactivation appears to be
characteristic of carriers of many gene mutations involved in XLMR
(Plenge et al., 2002). This prompted a search for an X-linked gene
involved in the syndrome in this family. Given the family's small size,
an inclusion-mapping strategy was performed. Genotyping of 36 markers
spaced at approximately 5 cM disclosed 3 loci, at Xq23-q25, harboring
alleles shared by all 3 affected males. Nascimento et al. (2006) found
30 genes within a narrowed candidate region that were expressed in
brain. However, only 1 of these gene, UBE2A, was expressed in both brain
and lymphocytes. Because of the skewed X-inactivation in the patients'
mothers, which likely represented the survival/proliferation advantage
of lymphocytes with the active normal allele in a woman with the
mutation, the authors sequenced the UBE2A gene and found a 382C-T
substitution leading to a premature stop codon (Q128X; 312180) in all 3
affected males and in their mothers. The sister of 1 of the affected
males, with a rather random X-inactivation pattern as documented by the
methylation status of the AR gene, did not carry this mutation. No
mutations in UBE2A were found in 19 idiopathic XLMR-affected families
mapped to intervals encompassing UBE2A.
In affected members of 2 unrelated families with syndromic XLMR, Budny
et al. (2010) identified 2 different missense mutations in the UBE2A
gene (312180.0002 and 312180.0003, respectively). The phenotype was
characterized by mental retardation and very poor speech, as well as
striking dysmorphic features, including large head, synophrys, prominent
supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide
mouth, myxedematous appearance, hirsutism, abnormal hair whorls,
micropenis, and onychodystrophy.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE
UBE2A, GLN128TER
In 3 males with an X-linked mental retardation syndrome (300860) in 3
sibships connected through carrier females in 2 generations, Nascimento
et al. (2006) identified a 382C-T transition in the UBE2A gene leading
to a premature UAG stop codon (gln128 to stop; Q128X). As a consequence
of the mutation, the predicted polypeptide lacked the 25 C-terminal
amino acid residues. The importance of this terminal sequence for UBE2
function was inferred by its conservation in vertebrates and in
Drosophila. No UBE2A mutations were found in 15 families with
nonsyndromic and 4 families with syndromic idiopathic XLMR previously
mapped to intervals encompassing this gene. This was the first
description of a mutation in a ubiquitin-conjugating enzyme gene as the
cause of a human disease. The affected males in the family presented a
neurodevelopmental disorder that included seizures, severe speech
impairment, marked general hirsutism, synophrys, and a low posterior
hairline.
.0002
MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE
UBE2A, GLY23ARG
In affected members of a large 5-generation family with X-linked
syndromic mental retardation (300860), Budny et al. (2010) identified a
67G-A transition in exon 2 of the UBE2A gene, resulting in a
gly23-to-arg (G23R) substitution in a highly conserved residue. The
mutation was not found in unaffected family members or in 168 male
controls. Three obligate female carriers showed skewed X-inactivation
profiles. The mutation was found by linkage analysis followed by
candidate gene sequencing. Functional studies were not performed.
.0003
MENTAL RETARDATION, X-LINKED, SYNDROMIC, NASCIMENTO TYPE
UBE2A, ARG11GLN
In 2 males from a family with X-linked syndromic mental retardation
(300860), Budny et al. (2010) identified a 32G-A transition in exon 1 of
the UBE2A gene, resulting in an arg11-to-gln (R11Q) substitution in a
highly conserved residue. The mutation was not found in unaffected
family members or in 168 male controls. Functional studies were not
performed.
*FIELD* RF
1. Budny, B.; Badura-Stronka, M.; Materna-Kiryluk, A.; Tzschach, A.;
Raynaud, M.; Latos-Bielenska, A.; Ropers, H. H.: Novel missense mutations
in the ubiquitination-related gene UBE2A cause a recognizable X-linked
mental retardation syndrome. Clin. Genet. 77: 541-551, 2010.
2. Hishida, T.; Kubota, Y.; Carr, A. M.; Iwasaki, H.: RAD6-RAD18-RAD5-pathway-dependent
tolerance to chronic low-dose ultraviolet light. Nature 457: 612-615,
2009.
3. Koken, M. H. M.; Reynolds, P.; Jaspers-Dekker, I.; Prakash, L.;
Prakash, S.; Bootsma, D.; Hoeijmakers, J. H. J.: Structural and functional
conservation of two human homologs of the yeast DNA repair gene RAD6. Proc.
Nat. Acad. Sci. 88: 8865-8869, 1991.
4. Koken, M. H. M.; Smit, E. M. E.; Jaspers-Dekker, I.; Oostra, B.
A.; Hagemeijer, A.; Bootsma, D.; Hoeijmakers, J. H. J.: Localization
of two human homologs, HHR6A and HHR6B, of the yeast DNA repair gene
RAD6 to chromosomes Xq24-q25 and 5q23-q31. Genomics 12: 447-453,
1992.
5. Nascimento, R. M. P.; Otto, P. A.; de Brouwer, A. P. M.; Vianna-Morgante,
A. M.: UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated
in a novel X-linked mental retardation syndrome. Am. J. Hum. Genet. 79:
549-555, 2006.
6. Plenge, R. M.; Stevenson, R. A.; Lubs, H. A.; Schwartz, C. E.;
Willard, H. F.: Skewed X-chromosome inactivation is a common feature
of X-linked mental retardation disorders. Am. J. Hum. Genet. 71:
168-173, 2002.
7. Ulrich, H. D.; Jentsch, S.: Two RING finger proteins mediate cooperation
between ubiquitin-conjugating enzymes in DNA repair. EMBO J. 19:
3388-3397, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/20/2011
Ada Hamosh - updated: 2/13/2009
Victor A. McKusick - updated: 8/23/2006
Ada Hamosh - updated: 11/21/2002
*FIELD* CD
Victor A. McKusick: 2/21/1992
*FIELD* ED
carol: 04/06/2012
carol: 12/22/2011
ckniffin: 12/20/2011
carol: 10/28/2011
carol: 10/26/2011
ckniffin: 10/25/2011
carol: 10/25/2011
alopez: 2/16/2009
terry: 2/13/2009
alopez: 1/29/2007
alopez: 8/28/2006
terry: 8/23/2006
alopez: 11/21/2002
terry: 11/18/2002
alopez: 3/4/1999
mark: 2/20/1997
mark: 10/26/1996
mark: 9/12/1995
carol: 3/17/1994
mimadm: 2/28/1994
supermim: 3/17/1992
carol: 3/2/1992