Full text data of UBA1
UBA1
(A1S9T, UBE1)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ubiquitin-like modifier-activating enzyme 1 (Protein A1S9; Ubiquitin-activating enzyme E1)
Ubiquitin-like modifier-activating enzyme 1 (Protein A1S9; Ubiquitin-activating enzyme E1)
UniProt
P22314
ID UBA1_HUMAN Reviewed; 1058 AA.
AC P22314; Q5JRR8; Q96E13;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-OCT-2002, sequence version 3.
DT 22-JAN-2014, entry version 159.
DE RecName: Full=Ubiquitin-like modifier-activating enzyme 1;
DE AltName: Full=Protein A1S9;
DE AltName: Full=Ubiquitin-activating enzyme E1;
GN Name=UBA1; Synonyms=A1S9T, UBE1;
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=1606621;
RA Ayusawa D., Kaneda S., Itoh Y., Yasuda H., Murakami Y., Sugasawa K.,
RA Hanaoka F., Seno T.;
RT "Complementation by a cloned human ubiquitin-activating enzyme E1 of
RT the S-phase-arrested mouse FM3A cell mutant with thermolabile E1.";
RL Cell Struct. Funct. 17:113-122(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 136-158; 369-383;
RP 417-430 AND 559-580.
RC TISSUE=Placenta;
RX PubMed=1986373; DOI=10.1073/pnas.88.1.258;
RA Handley P.M., Mueckler M., Siegel N.R., Ciechanover A., Schwartz A.L.;
RT "Molecular cloning, sequence, and tissue distribution of the human
RT ubiquitin-activating enzyme E1.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:258-262(1991).
RN [3]
RP ERRATUM.
RX PubMed=1871145;
RA Handley P.M., Mueckler M., Siegel N.R., Ciechanover A., Schwartz A.L.;
RL Proc. Natl. Acad. Sci. U.S.A. 88:7456-7456(1991).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 257-989.
RX PubMed=2390975;
RA Zacksenhaus E., Sheinin R.;
RT "Molecular cloning, primary structure and expression of the human X
RT linked A1S9 gene cDNA which complements the ts A1S9 mouse L cell
RT defect in DNA replication.";
RL EMBO J. 9:2923-2929(1990).
RN [8]
RP PROTEIN SEQUENCE OF 559-581 AND 924-944, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [9]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP INTERACTION WITH GAN.
RX PubMed=16227972; DOI=10.1038/nature04256;
RA Allen E., Ding J., Wang W., Pramanik S., Chou J., Yau V., Yang Y.;
RT "Gigaxonin-controlled degradation of MAP1B light chain is critical to
RT neuronal survival.";
RL Nature 438:224-228(2005).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-13; SER-46; THR-800 AND
RP SER-835, 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 [13]
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46 AND SER-810, 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 [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-671 AND LYS-980, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46 AND SER-810, AND MASS
RP 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 [17]
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 [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46, AND MASS
RP 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 [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP VARIANTS SMAX2 ILE-539 AND GLY-547.
RX PubMed=18179898; DOI=10.1016/j.ajhg.2007.09.009;
RA Ramser J., Ahearn M.E., Lenski C., Yariz K.O., Hellebrand H.,
RA von Rhein M., Clark R.D., Schmutzler R.K., Lichtner P., Hoffman E.P.,
RA Meindl A., Baumbach-Reardon L.;
RT "Rare missense and synonymous variants in UBE1 are associated with X-
RT linked infantile spinal muscular atrophy.";
RL Am. J. Hum. Genet. 82:188-193(2008).
CC -!- FUNCTION: Activates ubiquitin by first adenylating its C-terminal
CC glycine residue with ATP, and thereafter linking this residue to
CC the side chain of a cysteine residue in E1, yielding an ubiquitin-
CC E1 thioester and free AMP.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Monomer (By similarity). Interacts with GAN (via BTB
CC domain).
CC -!- INTERACTION:
CC Q76353:- (xeno); NbExp=2; IntAct=EBI-709688, EBI-6248077;
CC Q9H2C0:GAN; NbExp=5; IntAct=EBI-709688, EBI-764342;
CC P63279:UBE2I; NbExp=2; IntAct=EBI-709688, EBI-80168;
CC -!- PTM: ISGylated.
CC -!- DISEASE: Spinal muscular atrophy X-linked 2 (SMAX2) [MIM:301830]:
CC A lethal infantile form of spinal muscular atrophy, a
CC neuromuscular disorder characterized by degeneration of the
CC anterior horn cells of the spinal cord, leading to symmetrical
CC muscle weakness and atrophy. Clinical features include hypotonia,
CC areflexia, and multiple congenital contractures. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: There are two active sites within the E1 molecule,
CC allowing it to accommodate two ubiquitin moieties at a time, with
CC a new ubiquitin forming an adenylate intermediate as the previous
CC one is transferred to the thiol site.
CC -!- SIMILARITY: Belongs to the ubiquitin-activating E1 family.
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DR EMBL; X56976; CAA40296.1; -; mRNA.
DR EMBL; M58028; AAA61246.1; -; mRNA.
DR EMBL; AL513366; CAI41708.1; -; Genomic_DNA.
DR EMBL; CH471164; EAW59290.1; -; Genomic_DNA.
DR EMBL; BC013041; AAH13041.1; -; mRNA.
DR EMBL; X52897; CAA37078.1; -; mRNA.
DR PIR; A38564; A38564.
DR RefSeq; NP_003325.2; NM_003334.3.
DR RefSeq; NP_695012.1; NM_153280.2.
DR RefSeq; XP_005272707.1; XM_005272650.1.
DR RefSeq; XP_005278370.1; XM_005278313.1.
DR UniGene; Hs.533273; -.
DR ProteinModelPortal; P22314; -.
DR SMR; P22314; 50-1053.
DR DIP; DIP-33686N; -.
DR IntAct; P22314; 28.
DR MINT; MINT-1130980; -.
DR STRING; 9606.ENSP00000338413; -.
DR ChEMBL; CHEMBL5924; -.
DR PhosphoSite; P22314; -.
DR DMDM; 24418865; -.
DR REPRODUCTION-2DPAGE; IPI00645078; -.
DR PaxDb; P22314; -.
DR PeptideAtlas; P22314; -.
DR PRIDE; P22314; -.
DR DNASU; 7317; -.
DR Ensembl; ENST00000335972; ENSP00000338413; ENSG00000130985.
DR Ensembl; ENST00000377351; ENSP00000366568; ENSG00000130985.
DR Ensembl; ENST00000604887; ENSP00000474569; ENSG00000271310.
DR Ensembl; ENST00000605619; ENSP00000474757; ENSG00000271310.
DR GeneID; 7317; -.
DR KEGG; hsa:7317; -.
DR UCSC; uc004dhj.4; human.
DR CTD; 7317; -.
DR GeneCards; GC0XP047050; -.
DR HGNC; HGNC:12469; UBA1.
DR HPA; CAB019435; -.
DR HPA; HPA000289; -.
DR MIM; 301830; phenotype.
DR MIM; 314370; gene.
DR neXtProt; NX_P22314; -.
DR Orphanet; 1145; X-linked distal arthrogryposis multiplex congenita.
DR PharmGKB; PA37119; -.
DR eggNOG; COG0476; -.
DR HOGENOM; HOG000167329; -.
DR HOVERGEN; HBG054199; -.
DR InParanoid; P22314; -.
DR KO; K03178; -.
DR OMA; PFFAFSE; -.
DR OrthoDB; EOG74R1PV; -.
DR PhylomeDB; P22314; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; UBA1; human.
DR GeneWiki; UBA1; -.
DR GenomeRNAi; 7317; -.
DR NextBio; 28604; -.
DR PRO; PR:P22314; -.
DR ArrayExpress; P22314; -.
DR Bgee; P22314; -.
DR CleanEx; HS_UBA1; -.
DR Genevestigator; P22314; -.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0008641; F:small protein activating enzyme activity; IEA:InterPro.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.3240.10; -; 1.
DR Gene3D; 3.40.50.720; -; 4.
DR InterPro; IPR009036; Molybdenum_cofac_synth_MoeB.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR000594; ThiF_NAD_FAD-bd.
DR InterPro; IPR018965; Ub-activating_enz_e1_C.
DR InterPro; IPR023280; Ub-like_act_enz_cat_cys_dom.
DR InterPro; IPR000127; UBact_repeat.
DR InterPro; IPR019572; Ubiquitin-activating_enzyme.
DR InterPro; IPR018075; UBQ-activ_enz_E1.
DR InterPro; IPR018074; UBQ-activ_enz_E1_AS.
DR InterPro; IPR000011; UBQ/SUMO-activ_enz_E1-like.
DR Pfam; PF00899; ThiF; 2.
DR Pfam; PF09358; UBA_e1_C; 1.
DR Pfam; PF10585; UBA_e1_thiolCys; 1.
DR Pfam; PF02134; UBACT; 2.
DR PRINTS; PR01849; UBIQUITINACT.
DR SMART; SM00985; UBA_e1_C; 1.
DR SUPFAM; SSF69572; SSF69572; 2.
DR TIGRFAMs; TIGR01408; Ube1; 1.
DR PROSITE; PS00536; UBIQUITIN_ACTIVAT_1; 1.
DR PROSITE; PS00865; UBIQUITIN_ACTIVAT_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Complete proteome;
KW Direct protein sequencing; Disease mutation; Ligase;
KW Neurodegeneration; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1058 Ubiquitin-like modifier-activating enzyme
FT 1.
FT /FTId=PRO_0000194934.
FT REPEAT 63 199 1-1.
FT REPEAT 459 611 1-2.
FT NP_BIND 478 507 ATP (By similarity).
FT REGION 63 611 2 approximate repeats.
FT ACT_SITE 632 632 Glycyl thioester intermediate (By
FT similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 13 13 Phosphoserine.
FT MOD_RES 46 46 Phosphoserine.
FT MOD_RES 55 55 Phosphotyrosine (By similarity).
FT MOD_RES 671 671 N6-acetyllysine.
FT MOD_RES 800 800 Phosphothreonine.
FT MOD_RES 810 810 Phosphoserine.
FT MOD_RES 816 816 Phosphoserine (By similarity).
FT MOD_RES 820 820 Phosphoserine (By similarity).
FT MOD_RES 835 835 Phosphoserine.
FT MOD_RES 980 980 N6-acetyllysine.
FT VARIANT 447 447 R -> H (in dbSNP:rs2070169).
FT /FTId=VAR_043500.
FT VARIANT 539 539 M -> I (in SMAX2).
FT /FTId=VAR_043501.
FT VARIANT 547 547 S -> G (in SMAX2).
FT /FTId=VAR_043502.
FT CONFLICT 190 190 D -> G (in Ref. 1; CAA40296).
FT CONFLICT 434 434 E -> Q (in Ref. 1; CAA40296).
SQ SEQUENCE 1058 AA; 117849 MW; 4B413AAA75FAA562 CRC64;
MSSSPLSKKR RVSGPDPKPG SNCSPAQSVL SEVPSVPTNG MAKNGSEADI DEGLYSRQLY
VLGHEAMKRL QTSSVLVSGL RGLGVEIAKN IILGGVKAVT LHDQGTAQWA DLSSQFYLRE
EDIGKNRAEV SQPRLAELNS YVPVTAYTGP LVEDFLSGFQ VVVLTNTPLE DQLRVGEFCH
NRGIKLVVAD TRGLFGQLFC DFGEEMILTD SNGEQPLSAM VSMVTKDNPG VVTCLDEARH
GFESGDFVSF SEVQGMVELN GNQPMEIKVL GPYTFSICDT SNFSDYIRGG IVSQVKVPKK
ISFKSLVASL AEPDFVVTDF AKFSRPAQLH IGFQALHQFC AQHGRPPRPR NEEDAAELVA
LAQAVNARAL PAVQQNNLDE DLIRKLAYVA AGDLAPINAF IGGLAAQEVM KACSGKFMPI
MQWLYFDALE CLPEDKEVLT EDKCLQRQNR YDGQVAVFGS DLQEKLGKQK YFLVGAGAIG
CELLKNFAMI GLGCGEGGEI IVTDMDTIEK SNLNRQFLFR PWDVTKLKSD TAAAAVRQMN
PHIRVTSHQN RVGPDTERIY DDDFFQNLDG VANALDNVDA RMYMDRRCVY YRKPLLESGT
LGTKGNVQVV IPFLTESYSS SQDPPEKSIP ICTLKNFPNA IEHTLQWARD EFEGLFKQPA
ENVNQYLTDP KFVERTLRLA GTQPLEVLEA VQRSLVLQRP QTWADCVTWA CHHWHTQYSN
NIRQLLHNFP PDQLTSSGAP FWSGPKRCPH PLTFDVNNPL HLDYVMAAAN LFAQTYGLTG
SQDRAAVATF LQSVQVPEFT PKSGVKIHVS DQELQSANAS VDDSRLEELK ATLPSPDKLP
GFKMYPIDFE KDDDSNFHMD FIVAASNLRA ENYDIPSADR HKSKLIAGKI IPAIATTTAA
VVGLVCLELY KVVQGHRQLD SYKNGFLNLA LPFFGFSEPL AAPRHQYYNQ EWTLWDRFEV
QGLQPNGEEM TLKQFLDYFK TEHKLEITML SQGVSMLYSF FMPAAKLKER LDQPMTEIVS
RVSKRKLGRH VRALVLELCC NDESGEDVEV PYVRYTIR
//
ID UBA1_HUMAN Reviewed; 1058 AA.
AC P22314; Q5JRR8; Q96E13;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-OCT-2002, sequence version 3.
DT 22-JAN-2014, entry version 159.
DE RecName: Full=Ubiquitin-like modifier-activating enzyme 1;
DE AltName: Full=Protein A1S9;
DE AltName: Full=Ubiquitin-activating enzyme E1;
GN Name=UBA1; Synonyms=A1S9T, UBE1;
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=1606621;
RA Ayusawa D., Kaneda S., Itoh Y., Yasuda H., Murakami Y., Sugasawa K.,
RA Hanaoka F., Seno T.;
RT "Complementation by a cloned human ubiquitin-activating enzyme E1 of
RT the S-phase-arrested mouse FM3A cell mutant with thermolabile E1.";
RL Cell Struct. Funct. 17:113-122(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 136-158; 369-383;
RP 417-430 AND 559-580.
RC TISSUE=Placenta;
RX PubMed=1986373; DOI=10.1073/pnas.88.1.258;
RA Handley P.M., Mueckler M., Siegel N.R., Ciechanover A., Schwartz A.L.;
RT "Molecular cloning, sequence, and tissue distribution of the human
RT ubiquitin-activating enzyme E1.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:258-262(1991).
RN [3]
RP ERRATUM.
RX PubMed=1871145;
RA Handley P.M., Mueckler M., Siegel N.R., Ciechanover A., Schwartz A.L.;
RL Proc. Natl. Acad. Sci. U.S.A. 88:7456-7456(1991).
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 257-989.
RX PubMed=2390975;
RA Zacksenhaus E., Sheinin R.;
RT "Molecular cloning, primary structure and expression of the human X
RT linked A1S9 gene cDNA which complements the ts A1S9 mouse L cell
RT defect in DNA replication.";
RL EMBO J. 9:2923-2929(1990).
RN [8]
RP PROTEIN SEQUENCE OF 559-581 AND 924-944, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [9]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [11]
RP INTERACTION WITH GAN.
RX PubMed=16227972; DOI=10.1038/nature04256;
RA Allen E., Ding J., Wang W., Pramanik S., Chou J., Yau V., Yang Y.;
RT "Gigaxonin-controlled degradation of MAP1B light chain is critical to
RT neuronal survival.";
RL Nature 438:224-228(2005).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-13; SER-46; THR-800 AND
RP SER-835, 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 [13]
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46 AND SER-810, 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 [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-671 AND LYS-980, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46 AND SER-810, AND MASS
RP 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 [17]
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 [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-46, AND MASS
RP 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 [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP VARIANTS SMAX2 ILE-539 AND GLY-547.
RX PubMed=18179898; DOI=10.1016/j.ajhg.2007.09.009;
RA Ramser J., Ahearn M.E., Lenski C., Yariz K.O., Hellebrand H.,
RA von Rhein M., Clark R.D., Schmutzler R.K., Lichtner P., Hoffman E.P.,
RA Meindl A., Baumbach-Reardon L.;
RT "Rare missense and synonymous variants in UBE1 are associated with X-
RT linked infantile spinal muscular atrophy.";
RL Am. J. Hum. Genet. 82:188-193(2008).
CC -!- FUNCTION: Activates ubiquitin by first adenylating its C-terminal
CC glycine residue with ATP, and thereafter linking this residue to
CC the side chain of a cysteine residue in E1, yielding an ubiquitin-
CC E1 thioester and free AMP.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Monomer (By similarity). Interacts with GAN (via BTB
CC domain).
CC -!- INTERACTION:
CC Q76353:- (xeno); NbExp=2; IntAct=EBI-709688, EBI-6248077;
CC Q9H2C0:GAN; NbExp=5; IntAct=EBI-709688, EBI-764342;
CC P63279:UBE2I; NbExp=2; IntAct=EBI-709688, EBI-80168;
CC -!- PTM: ISGylated.
CC -!- DISEASE: Spinal muscular atrophy X-linked 2 (SMAX2) [MIM:301830]:
CC A lethal infantile form of spinal muscular atrophy, a
CC neuromuscular disorder characterized by degeneration of the
CC anterior horn cells of the spinal cord, leading to symmetrical
CC muscle weakness and atrophy. Clinical features include hypotonia,
CC areflexia, and multiple congenital contractures. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: There are two active sites within the E1 molecule,
CC allowing it to accommodate two ubiquitin moieties at a time, with
CC a new ubiquitin forming an adenylate intermediate as the previous
CC one is transferred to the thiol site.
CC -!- SIMILARITY: Belongs to the ubiquitin-activating E1 family.
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DR EMBL; X56976; CAA40296.1; -; mRNA.
DR EMBL; M58028; AAA61246.1; -; mRNA.
DR EMBL; AL513366; CAI41708.1; -; Genomic_DNA.
DR EMBL; CH471164; EAW59290.1; -; Genomic_DNA.
DR EMBL; BC013041; AAH13041.1; -; mRNA.
DR EMBL; X52897; CAA37078.1; -; mRNA.
DR PIR; A38564; A38564.
DR RefSeq; NP_003325.2; NM_003334.3.
DR RefSeq; NP_695012.1; NM_153280.2.
DR RefSeq; XP_005272707.1; XM_005272650.1.
DR RefSeq; XP_005278370.1; XM_005278313.1.
DR UniGene; Hs.533273; -.
DR ProteinModelPortal; P22314; -.
DR SMR; P22314; 50-1053.
DR DIP; DIP-33686N; -.
DR IntAct; P22314; 28.
DR MINT; MINT-1130980; -.
DR STRING; 9606.ENSP00000338413; -.
DR ChEMBL; CHEMBL5924; -.
DR PhosphoSite; P22314; -.
DR DMDM; 24418865; -.
DR REPRODUCTION-2DPAGE; IPI00645078; -.
DR PaxDb; P22314; -.
DR PeptideAtlas; P22314; -.
DR PRIDE; P22314; -.
DR DNASU; 7317; -.
DR Ensembl; ENST00000335972; ENSP00000338413; ENSG00000130985.
DR Ensembl; ENST00000377351; ENSP00000366568; ENSG00000130985.
DR Ensembl; ENST00000604887; ENSP00000474569; ENSG00000271310.
DR Ensembl; ENST00000605619; ENSP00000474757; ENSG00000271310.
DR GeneID; 7317; -.
DR KEGG; hsa:7317; -.
DR UCSC; uc004dhj.4; human.
DR CTD; 7317; -.
DR GeneCards; GC0XP047050; -.
DR HGNC; HGNC:12469; UBA1.
DR HPA; CAB019435; -.
DR HPA; HPA000289; -.
DR MIM; 301830; phenotype.
DR MIM; 314370; gene.
DR neXtProt; NX_P22314; -.
DR Orphanet; 1145; X-linked distal arthrogryposis multiplex congenita.
DR PharmGKB; PA37119; -.
DR eggNOG; COG0476; -.
DR HOGENOM; HOG000167329; -.
DR HOVERGEN; HBG054199; -.
DR InParanoid; P22314; -.
DR KO; K03178; -.
DR OMA; PFFAFSE; -.
DR OrthoDB; EOG74R1PV; -.
DR PhylomeDB; P22314; -.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; UBA1; human.
DR GeneWiki; UBA1; -.
DR GenomeRNAi; 7317; -.
DR NextBio; 28604; -.
DR PRO; PR:P22314; -.
DR ArrayExpress; P22314; -.
DR Bgee; P22314; -.
DR CleanEx; HS_UBA1; -.
DR Genevestigator; P22314; -.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0008641; F:small protein activating enzyme activity; IEA:InterPro.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.3240.10; -; 1.
DR Gene3D; 3.40.50.720; -; 4.
DR InterPro; IPR009036; Molybdenum_cofac_synth_MoeB.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR000594; ThiF_NAD_FAD-bd.
DR InterPro; IPR018965; Ub-activating_enz_e1_C.
DR InterPro; IPR023280; Ub-like_act_enz_cat_cys_dom.
DR InterPro; IPR000127; UBact_repeat.
DR InterPro; IPR019572; Ubiquitin-activating_enzyme.
DR InterPro; IPR018075; UBQ-activ_enz_E1.
DR InterPro; IPR018074; UBQ-activ_enz_E1_AS.
DR InterPro; IPR000011; UBQ/SUMO-activ_enz_E1-like.
DR Pfam; PF00899; ThiF; 2.
DR Pfam; PF09358; UBA_e1_C; 1.
DR Pfam; PF10585; UBA_e1_thiolCys; 1.
DR Pfam; PF02134; UBACT; 2.
DR PRINTS; PR01849; UBIQUITINACT.
DR SMART; SM00985; UBA_e1_C; 1.
DR SUPFAM; SSF69572; SSF69572; 2.
DR TIGRFAMs; TIGR01408; Ube1; 1.
DR PROSITE; PS00536; UBIQUITIN_ACTIVAT_1; 1.
DR PROSITE; PS00865; UBIQUITIN_ACTIVAT_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Complete proteome;
KW Direct protein sequencing; Disease mutation; Ligase;
KW Neurodegeneration; Nucleotide-binding; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1058 Ubiquitin-like modifier-activating enzyme
FT 1.
FT /FTId=PRO_0000194934.
FT REPEAT 63 199 1-1.
FT REPEAT 459 611 1-2.
FT NP_BIND 478 507 ATP (By similarity).
FT REGION 63 611 2 approximate repeats.
FT ACT_SITE 632 632 Glycyl thioester intermediate (By
FT similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 13 13 Phosphoserine.
FT MOD_RES 46 46 Phosphoserine.
FT MOD_RES 55 55 Phosphotyrosine (By similarity).
FT MOD_RES 671 671 N6-acetyllysine.
FT MOD_RES 800 800 Phosphothreonine.
FT MOD_RES 810 810 Phosphoserine.
FT MOD_RES 816 816 Phosphoserine (By similarity).
FT MOD_RES 820 820 Phosphoserine (By similarity).
FT MOD_RES 835 835 Phosphoserine.
FT MOD_RES 980 980 N6-acetyllysine.
FT VARIANT 447 447 R -> H (in dbSNP:rs2070169).
FT /FTId=VAR_043500.
FT VARIANT 539 539 M -> I (in SMAX2).
FT /FTId=VAR_043501.
FT VARIANT 547 547 S -> G (in SMAX2).
FT /FTId=VAR_043502.
FT CONFLICT 190 190 D -> G (in Ref. 1; CAA40296).
FT CONFLICT 434 434 E -> Q (in Ref. 1; CAA40296).
SQ SEQUENCE 1058 AA; 117849 MW; 4B413AAA75FAA562 CRC64;
MSSSPLSKKR RVSGPDPKPG SNCSPAQSVL SEVPSVPTNG MAKNGSEADI DEGLYSRQLY
VLGHEAMKRL QTSSVLVSGL RGLGVEIAKN IILGGVKAVT LHDQGTAQWA DLSSQFYLRE
EDIGKNRAEV SQPRLAELNS YVPVTAYTGP LVEDFLSGFQ VVVLTNTPLE DQLRVGEFCH
NRGIKLVVAD TRGLFGQLFC DFGEEMILTD SNGEQPLSAM VSMVTKDNPG VVTCLDEARH
GFESGDFVSF SEVQGMVELN GNQPMEIKVL GPYTFSICDT SNFSDYIRGG IVSQVKVPKK
ISFKSLVASL AEPDFVVTDF AKFSRPAQLH IGFQALHQFC AQHGRPPRPR NEEDAAELVA
LAQAVNARAL PAVQQNNLDE DLIRKLAYVA AGDLAPINAF IGGLAAQEVM KACSGKFMPI
MQWLYFDALE CLPEDKEVLT EDKCLQRQNR YDGQVAVFGS DLQEKLGKQK YFLVGAGAIG
CELLKNFAMI GLGCGEGGEI IVTDMDTIEK SNLNRQFLFR PWDVTKLKSD TAAAAVRQMN
PHIRVTSHQN RVGPDTERIY DDDFFQNLDG VANALDNVDA RMYMDRRCVY YRKPLLESGT
LGTKGNVQVV IPFLTESYSS SQDPPEKSIP ICTLKNFPNA IEHTLQWARD EFEGLFKQPA
ENVNQYLTDP KFVERTLRLA GTQPLEVLEA VQRSLVLQRP QTWADCVTWA CHHWHTQYSN
NIRQLLHNFP PDQLTSSGAP FWSGPKRCPH PLTFDVNNPL HLDYVMAAAN LFAQTYGLTG
SQDRAAVATF LQSVQVPEFT PKSGVKIHVS DQELQSANAS VDDSRLEELK ATLPSPDKLP
GFKMYPIDFE KDDDSNFHMD FIVAASNLRA ENYDIPSADR HKSKLIAGKI IPAIATTTAA
VVGLVCLELY KVVQGHRQLD SYKNGFLNLA LPFFGFSEPL AAPRHQYYNQ EWTLWDRFEV
QGLQPNGEEM TLKQFLDYFK TEHKLEITML SQGVSMLYSF FMPAAKLKER LDQPMTEIVS
RVSKRKLGRH VRALVLELCC NDESGEDVEV PYVRYTIR
//
MIM
301830
*RECORD*
*FIELD* NO
301830
*FIELD* TI
#301830 SPINAL MUSCULAR ATROPHY, X-LINKED 2; SMAX2
;;SPINAL MUSCULAR ATROPHY, X-LINKED LETHAL INFANTILE;;
read moreSPINAL MUSCULAR ATROPHY, INFANTILE X-LINKED; XLSMA;;
ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, X-LINKED;;
AMC, DISTAL, X-LINKED;;
ARTHROGRYPOSIS, X-LINKED, TYPE I; AMCX1
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
X-linked form of infantile X-linked spinal muscular atrophy (SMAX2) is
caused by mutations in the UBE1 gene (314370) at Xp11.
DESCRIPTION
X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by
neonatal onset of severe hypotonia, areflexia, and multiple congenital
contractures, known as arthrogryposis, associated with loss of anterior
horn cells and infantile death (summary by Ramser et al., 2008).
Historically, Hall et al. (1982) distinguished at least 3 clinical
varieties of X-linked arthrogryposis. (1) One family had a severe lethal
form with severe contractures, scoliosis, chest deformities, hypotonia,
micrognathia, and death from respiratory insufficiency by age 3 months.
Apparently progressive loss of anterior horn cells was the cause. (2)
Two families had moderately severe AMC associated with ptosis,
microphallus, cryptorchidism, inguinal hernias, and normal intelligence.
Nonprogressive intrauterine myopathy appeared to be the 'cause'. (3) In
2 families and a sporadic case, the disorder took the form of a
resolving AMC, with mild to moderate contractures improving dramatically
with time, normal intelligence, and no other anomalies; tight connective
tissues on misplaced tendons was postulated.
CLINICAL FEATURES
Greenberg et al. (1988) described under the label 'X-linked infantile
spinal muscular atrophy' a disorder which appeared to be X-linked and
was associated with contractures as in X-linked arthrogryposis.
Kobayashi et al. (1995) studied the family originally reported by
Greenberg et al. (1988). Affected individuals showed hypotonia,
areflexia, chest deformities, facial dysmorphic features, and congenital
joint contractures. The findings of electromyography and muscle biopsy
were consistent with loss of anterior horn cells as in autosomal
recessive infantile spinal muscular atrophy (253300). At the time of the
linkage study by Kobayashi et al. (1995), 1 affected male was living at
age 13 years, whereas the other affected males died within the first 2
years of life.
Baumbach et al. (1994) described an X-linked form of proximal spinal
muscular atrophy in 2 unrelated multigeneration families with similar
clinical presentations of severe hypotonia, muscle weakness, and a
disease course similar to that of Werdnig-Hoffmann disease (253300)
except for the additional finding of congenital or early-onset
contractures. Muscle biopsy and/or autopsy indicated anterior horn cell
loss in affected males. The pedigree pattern in this and 2 additional
families was that of an X-linked recessive disorder. Several sporadic
male cases were also identified.
MAPPING
By linkage studies in 2 families with an X-linked form of proximal
spinal muscular atrophy, Baumbach et al. (1994) identified two 16-cM
regions on Xp with complete concordance to the disease phenotype. One of
these regions surrounded the Kallmann gene (KAL1; 300836). The remainder
of the X chromosome was excluded, including the locus for the Kennedy
type of spinal and bulbar muscular atrophy (SMAX1; 313200).
Kobayashi et al. (1995) demonstrated linkage of the disorder in the
family reported by Greenberg et al. (1988) to markers in the region of
the centromere of the X chromosome: Xp11.3-q11.2.
Dressman et al. (2007) studied 7 new families with new markers and
narrowed the gene interval for the XLSMA locus on Xp11.3-q11.1.
MOLECULAR GENETICS
To identify the XLSMA disease gene, Ramser et al. (2008) performed
large-scale mutation analysis in genes located between markers DXS8080
and DXS7132 on Xp11.3-q11.1. This resulted in detection of 3 rare novel
variants in exon 15 of the gene encoding ubiquitin-activating enzyme-1
(UBE1; 314370) that segregated with the disease. Two of the mutations
were missense mutations (314370.0001, 314370.0002), and the third was a
synonymous C-to-T substitution (314370.0003) that led to significant
reduction of UBE1 expression with alteration in the methylation pattern
of exon 15, implying a plausible role of this DNA element in
developmental UBE1 expression in humans. Thus, XLSMA is one of several
neurodegenerative disorders associated with defects in the
ubiquitin-proteasome pathway; these disorders include Parkinson disease
with mutations in PARK2 (602544) and UCHL1 (191342), and a distinctive
X-linked form of mental retardation (300354) caused by mutations in
CUL4B (300304). The experience of the authors indicated that synonymous
C-to-T transitions have the potential to affect gene expression.
NOMENCLATURE
The provisional symbol SMAX2 is used for this disorder, since Kennedy
disease (SMAX1; 313200) represents the first recognized form of X-linked
spinal muscular atrophy.
*FIELD* RF
1. Baumbach, L.; Best, B.; Edwards, J.; Schiavi, A.; Greenberg, F.
: X-linked lethal infantile spinal muscular atrophy: from clinical
description to molecular mapping. (Abstract) Am. J. Hum. Genet. 55
(suppl.): A211, 1994.
2. Dressman, D.; Ahearn, M. E.; Yariz, K. O.; Basterrecha, H.; Martinez,
F.; Palau, F.; Barmada, M. M.; Clark, R. D.; Meindl, A.; Wirth, B.;
Hoffman, E. P.; Baumbach-Reardon, L.: X-linked infantile spinal muscular
atrophy: clinical definition and molecular mapping. Genet. Med. 9:
52-60, 2007.
3. Greenberg, F.; Fenolio, K. R.; Hejtmancik, J. F.; Armstrong, D.;
Willis, J. K.; Shapira, E.; Huntington, H. W.; Haun, R. L.: X-linked
infantile spinal muscular atrophy. Am. J. Dis. Child. 142: 217-219,
1988.
4. Hall, J. G.; Reed, S. D.; Scott, C. I.; Rogers, J. G.; Jones, K.
L.; Camarano, A.: Three distinct types of X-linked arthrogryposis
seen in 6 families. Clin. Genet. 21: 81-97, 1982.
5. Kobayashi, H.; Baumbach, L.; Cox Matise, T.; Schiavi, A.; Greenberg,
F.; Hoffman, E. P.: A gene for a severe lethal form of X-linked arthrogryposis
(X-linked infantile spinal muscular atrophy) maps to human chromosome
Xp11.3-q11.2. Hum. Molec. Genet. 4: 1213-1216, 1995.
6. Ramser, J.; Ahearn, M. E.; Lenski, C.; Yariz, K. O.; Hellebrand,
H.; von Rhein, M.; Clark, R. D.; Schmutzler, R. K.; Lichtner, P.;
Hoffman, E. P.; Meindl, A.; Baumbach-Reardon, L.: Rare missense and
synonymous variants in UBE1 are associated with X-linked infantile
spinal muscular atrophy. Am. J. Hum. Genet. 82: 188-193, 2008.
*FIELD* CS
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Face];
Myopathic facies;
Facial weakness;
[Mouth];
Tongue fasciculations
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
CHEST:
[External features];
Chest deformities
GENITOURINARY:
[External genitalia, male];
Hypospadias;
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
Arthrogryposis;
Multiple joint contractures;
Bone fractures (at birth and postnatal);
[Skull];
Dysmorphic skull;
[Hands];
Digital contractures
MUSCLE, SOFT TISSUE:
Hypotonia, severe;
Muscle biopsy shows neurogenic atrophy affecting both fibers types;
Denervation of skeletal muscles
NEUROLOGIC:
[Central nervous system];
Hypotonia, severe;
Loss of anterior horn cells;
[Peripheral nervous system];
Areflexia
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
MISCELLANEOUS:
Death usually in infancy due to respiratory failure;
Increased spontaneous abortions in carrier mothers
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-like modifier-activating enzyme
1 gene (UBA1, 314370.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 10/17/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 10/17/2012
ckniffin: 10/17/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 6/13/2013
Victor A. McKusick - updated: 2/19/2008
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 06/19/2013
ckniffin: 6/13/2013
alopez: 3/10/2011
alopez: 6/26/2008
alopez: 2/27/2008
terry: 2/19/2008
joanna: 4/21/2004
ckniffin: 3/29/2004
carol: 3/17/2004
alopez: 12/22/1998
alopez: 11/9/1998
mark: 9/12/1995
mimadm: 2/27/1994
supermim: 3/17/1992
carol: 10/1/1991
supermim: 3/20/1990
ddp: 10/26/1989
*RECORD*
*FIELD* NO
301830
*FIELD* TI
#301830 SPINAL MUSCULAR ATROPHY, X-LINKED 2; SMAX2
;;SPINAL MUSCULAR ATROPHY, X-LINKED LETHAL INFANTILE;;
read moreSPINAL MUSCULAR ATROPHY, INFANTILE X-LINKED; XLSMA;;
ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, X-LINKED;;
AMC, DISTAL, X-LINKED;;
ARTHROGRYPOSIS, X-LINKED, TYPE I; AMCX1
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
X-linked form of infantile X-linked spinal muscular atrophy (SMAX2) is
caused by mutations in the UBE1 gene (314370) at Xp11.
DESCRIPTION
X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by
neonatal onset of severe hypotonia, areflexia, and multiple congenital
contractures, known as arthrogryposis, associated with loss of anterior
horn cells and infantile death (summary by Ramser et al., 2008).
Historically, Hall et al. (1982) distinguished at least 3 clinical
varieties of X-linked arthrogryposis. (1) One family had a severe lethal
form with severe contractures, scoliosis, chest deformities, hypotonia,
micrognathia, and death from respiratory insufficiency by age 3 months.
Apparently progressive loss of anterior horn cells was the cause. (2)
Two families had moderately severe AMC associated with ptosis,
microphallus, cryptorchidism, inguinal hernias, and normal intelligence.
Nonprogressive intrauterine myopathy appeared to be the 'cause'. (3) In
2 families and a sporadic case, the disorder took the form of a
resolving AMC, with mild to moderate contractures improving dramatically
with time, normal intelligence, and no other anomalies; tight connective
tissues on misplaced tendons was postulated.
CLINICAL FEATURES
Greenberg et al. (1988) described under the label 'X-linked infantile
spinal muscular atrophy' a disorder which appeared to be X-linked and
was associated with contractures as in X-linked arthrogryposis.
Kobayashi et al. (1995) studied the family originally reported by
Greenberg et al. (1988). Affected individuals showed hypotonia,
areflexia, chest deformities, facial dysmorphic features, and congenital
joint contractures. The findings of electromyography and muscle biopsy
were consistent with loss of anterior horn cells as in autosomal
recessive infantile spinal muscular atrophy (253300). At the time of the
linkage study by Kobayashi et al. (1995), 1 affected male was living at
age 13 years, whereas the other affected males died within the first 2
years of life.
Baumbach et al. (1994) described an X-linked form of proximal spinal
muscular atrophy in 2 unrelated multigeneration families with similar
clinical presentations of severe hypotonia, muscle weakness, and a
disease course similar to that of Werdnig-Hoffmann disease (253300)
except for the additional finding of congenital or early-onset
contractures. Muscle biopsy and/or autopsy indicated anterior horn cell
loss in affected males. The pedigree pattern in this and 2 additional
families was that of an X-linked recessive disorder. Several sporadic
male cases were also identified.
MAPPING
By linkage studies in 2 families with an X-linked form of proximal
spinal muscular atrophy, Baumbach et al. (1994) identified two 16-cM
regions on Xp with complete concordance to the disease phenotype. One of
these regions surrounded the Kallmann gene (KAL1; 300836). The remainder
of the X chromosome was excluded, including the locus for the Kennedy
type of spinal and bulbar muscular atrophy (SMAX1; 313200).
Kobayashi et al. (1995) demonstrated linkage of the disorder in the
family reported by Greenberg et al. (1988) to markers in the region of
the centromere of the X chromosome: Xp11.3-q11.2.
Dressman et al. (2007) studied 7 new families with new markers and
narrowed the gene interval for the XLSMA locus on Xp11.3-q11.1.
MOLECULAR GENETICS
To identify the XLSMA disease gene, Ramser et al. (2008) performed
large-scale mutation analysis in genes located between markers DXS8080
and DXS7132 on Xp11.3-q11.1. This resulted in detection of 3 rare novel
variants in exon 15 of the gene encoding ubiquitin-activating enzyme-1
(UBE1; 314370) that segregated with the disease. Two of the mutations
were missense mutations (314370.0001, 314370.0002), and the third was a
synonymous C-to-T substitution (314370.0003) that led to significant
reduction of UBE1 expression with alteration in the methylation pattern
of exon 15, implying a plausible role of this DNA element in
developmental UBE1 expression in humans. Thus, XLSMA is one of several
neurodegenerative disorders associated with defects in the
ubiquitin-proteasome pathway; these disorders include Parkinson disease
with mutations in PARK2 (602544) and UCHL1 (191342), and a distinctive
X-linked form of mental retardation (300354) caused by mutations in
CUL4B (300304). The experience of the authors indicated that synonymous
C-to-T transitions have the potential to affect gene expression.
NOMENCLATURE
The provisional symbol SMAX2 is used for this disorder, since Kennedy
disease (SMAX1; 313200) represents the first recognized form of X-linked
spinal muscular atrophy.
*FIELD* RF
1. Baumbach, L.; Best, B.; Edwards, J.; Schiavi, A.; Greenberg, F.
: X-linked lethal infantile spinal muscular atrophy: from clinical
description to molecular mapping. (Abstract) Am. J. Hum. Genet. 55
(suppl.): A211, 1994.
2. Dressman, D.; Ahearn, M. E.; Yariz, K. O.; Basterrecha, H.; Martinez,
F.; Palau, F.; Barmada, M. M.; Clark, R. D.; Meindl, A.; Wirth, B.;
Hoffman, E. P.; Baumbach-Reardon, L.: X-linked infantile spinal muscular
atrophy: clinical definition and molecular mapping. Genet. Med. 9:
52-60, 2007.
3. Greenberg, F.; Fenolio, K. R.; Hejtmancik, J. F.; Armstrong, D.;
Willis, J. K.; Shapira, E.; Huntington, H. W.; Haun, R. L.: X-linked
infantile spinal muscular atrophy. Am. J. Dis. Child. 142: 217-219,
1988.
4. Hall, J. G.; Reed, S. D.; Scott, C. I.; Rogers, J. G.; Jones, K.
L.; Camarano, A.: Three distinct types of X-linked arthrogryposis
seen in 6 families. Clin. Genet. 21: 81-97, 1982.
5. Kobayashi, H.; Baumbach, L.; Cox Matise, T.; Schiavi, A.; Greenberg,
F.; Hoffman, E. P.: A gene for a severe lethal form of X-linked arthrogryposis
(X-linked infantile spinal muscular atrophy) maps to human chromosome
Xp11.3-q11.2. Hum. Molec. Genet. 4: 1213-1216, 1995.
6. Ramser, J.; Ahearn, M. E.; Lenski, C.; Yariz, K. O.; Hellebrand,
H.; von Rhein, M.; Clark, R. D.; Schmutzler, R. K.; Lichtner, P.;
Hoffman, E. P.; Meindl, A.; Baumbach-Reardon, L.: Rare missense and
synonymous variants in UBE1 are associated with X-linked infantile
spinal muscular atrophy. Am. J. Hum. Genet. 82: 188-193, 2008.
*FIELD* CS
INHERITANCE:
X-linked recessive
HEAD AND NECK:
[Face];
Myopathic facies;
Facial weakness;
[Mouth];
Tongue fasciculations
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
CHEST:
[External features];
Chest deformities
GENITOURINARY:
[External genitalia, male];
Hypospadias;
[Internal genitalia, male];
Cryptorchidism
SKELETAL:
Arthrogryposis;
Multiple joint contractures;
Bone fractures (at birth and postnatal);
[Skull];
Dysmorphic skull;
[Hands];
Digital contractures
MUSCLE, SOFT TISSUE:
Hypotonia, severe;
Muscle biopsy shows neurogenic atrophy affecting both fibers types;
Denervation of skeletal muscles
NEUROLOGIC:
[Central nervous system];
Hypotonia, severe;
Loss of anterior horn cells;
[Peripheral nervous system];
Areflexia
PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movements
MISCELLANEOUS:
Death usually in infancy due to respiratory failure;
Increased spontaneous abortions in carrier mothers
MOLECULAR BASIS:
Caused by mutation in the ubiquitin-like modifier-activating enzyme
1 gene (UBA1, 314370.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 10/17/2012
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 10/17/2012
ckniffin: 10/17/2012
*FIELD* CN
Cassandra L. Kniffin - updated: 6/13/2013
Victor A. McKusick - updated: 2/19/2008
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 06/19/2013
ckniffin: 6/13/2013
alopez: 3/10/2011
alopez: 6/26/2008
alopez: 2/27/2008
terry: 2/19/2008
joanna: 4/21/2004
ckniffin: 3/29/2004
carol: 3/17/2004
alopez: 12/22/1998
alopez: 11/9/1998
mark: 9/12/1995
mimadm: 2/27/1994
supermim: 3/17/1992
carol: 10/1/1991
supermim: 3/20/1990
ddp: 10/26/1989
MIM
314370
*RECORD*
*FIELD* NO
314370
*FIELD* TI
*314370 UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 1; UBA1
;;UBIQUITIN-ACTIVATING ENZYME 1; UBE1;;
read moreBN75 TEMPERATURE SENSITIVITY COMPLEMENTING; GXP1
TEMPERATURE-SENSITIVE MUTATION, MOUSE, COMPLEMENTATION OF, INCLUDED;;
tsA1S9, INCLUDED;;
A1S9T, INCLUDED;;
A1S9, INCLUDED
*FIELD* TX
DESCRIPTION
Modification of proteins with ubiquitin (UBB; 191339) or ubiquitin-like
proteins controls many signaling networks and requires a ubiquitin
activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a
ubiquitin protein ligase (E3). UBA1 is an E1 enzyme that initiates the
activation and conjugation of ubiquitin-like proteins (Jin et al.,
2007).
CLONING
Zacksenhaus and Sheinin (1989) cloned the human A1S9 cDNA following
DNA-mediated gene transfer.
Handley et al. (1991) described the cloning and sequencing of the cDNA
for human E1, their term for the ubiquitin-activating enzyme catalyzing
the first step in ubiquitin conjugation. The cDNA recognized a single
3.5-kb E1 message that was ubiquitous among tissues and cell lines
studied. In vitro translation of the mRNA yielded a major product of
approximately 118 kD, which was immunoprecipitated by the antihuman E1
antibody used to identify the clone.
Jin et al. (2007) stated that the 1,058-amino acid UBE1 protein contains
an N-terminal adenylation domain with 2 ThiF-1 regions, a catalytic
cysteine domain, and a C-terminal ubiquitin-fold domain that functions
to recruit E2s. Database analysis detected variable UBE1 expression in
all human tissues and cell lines examined.
GENE STRUCTURE
The UBE1 gene comprises 27 exons, including an alternative first exon
designated 1a (Ramser et al., 2008). Translation begins in exon 2.
GENE FUNCTION
Jin et al. (2007) showed that UBE1 was able to transfer ubiquitin to a
wide range of E2 substrates.
Ohtsubo and Nishimoto (1988) studied 2 cell lines with a
temperature-sensitive (ts) defect in the S-phase of cell cycle. Two
lines failed to complement each other and therefore are presumed to have
the same defect as demonstrated in 1 of them: a ts defect in the
ubiquitin-activating enzyme. X-linkage was shown for one of the cell
lines by demonstration of cosegregation with HPRT in interspecies
somatic cell hybrids. The complicated nature of the genetic control of
cell growth reflected in ts mutants is indicated by the fact that 23
complementation groups have been identified by cell fusion analysis
using polyethylene glycol (Nishimoto and Basilico, 1978; Nishimoto et
al., 1982).
It turned out that the UBE1 locus is the same as that of the
temperature-sensitive gene called A1S9T. Willard et al. (1987) studied
the human gene that complements an X-linked mouse temperature-sensitive
defect in DNA synthesis; it is apparently different from the X-linked
factor represented by entry 313650 inasmuch as it was found to be
located on the short arm rather than on the long arm. The mouse mutant
tsA1S9 was characterized as a defect in DNA synthesis affecting
conversion of low molecular weight, newly synthesized DNA to mature
chromosomal DNA. In hybrid cells between normal human cells and mutant
mouse cells, it was found that the X chromosome and specifically the
short arm of the X chromosome complemented the defect. Brown et al.
(1989) and Brown and Willard (1989) found that a somatic hybrid cell
containing the region Xp21.1-p11.1 as its only X-chromosomal material
was able to survive at the nonpermissive temperature and thus must
contain the A1S9T gene. Since they had previously found that this gene
can be expressed from an inactive X chromosome (although not from the
Y), the new findings indicated that a second region of the human X
chromosome, in addition to the distal Xp22.3 location of other genes
that escape inactivation (MIC2, STS, XG), is also not subject to X
chromosome inactivation.
Zacksenhaus and Sheinin (1988) isolated a human gene complementing the
defect in a temperature-sensitive mouse L-cell line called ts A1S9. The
defect is in a gene required for nuclear DNA replication early in the S
phase of the cell cycle. DNA-mediated gene transfer (DMGT) was used and
the highly repetitive Alu family, which is present in at least 1 copy in
virtually every human gene, was used as a marker for the presence of the
human DNA in transfected mouse cells. Zacksenhaus and Sheinin (1988)
stated that this was the first demonstration of transfer of a human
S-phase gene. That the gene is X-linked was suggested by the fact that
both active and inactive human X chromosomes corrected the defect. The
authors quoted observations indicating that the tsA1S9 gene product is
not required for polydeoxyribonucleotide chain synthesis per se; thus,
the gene does not encode DNA polymerase alpha or DNA ligase. DNA
polymerase beta and gamma, as well as poly(ADP-ribose) polymerase, had
also been ruled out. Some evidence suggested that the temperature-labile
A1S9 protein may participate in DNA topoisomerase-2 activity.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich
elements in the 3-prime untranslated region. Rapid decay involves
AU-rich binding protein AUF1 (601324), which complexes with heat-shock
proteins HSC70 (600816) and HSP70 (see 140550), translation initiation
factor EIF4G (600495), and poly(A)-binding protein (604679). AU-rich
mRNA decay is associated with displacement of EIF4G from AUF1,
ubiquitination of AUF1, and degradation of AUF1 by proteasomes.
Induction of HSP70 by heat shock, downregulation of the
ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme
E1, all result in HSP70 sequestration of AUF1 in the
perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs
and AUF1 protein. These results link the rapid degradation of cytokine
mRNAs to the ubiquitin-proteasome pathway (Larola et al., 1999).
MAPPING
Using Southern blot and in situ hybridization, Zacksenhaus et al. (1989,
1990) mapped the A1S9 gene to Xp11.4-p11.2. On the basis of a study of
somatic cell hybrids with various deleted human X chromosomes, Brown and
Willard (1990) gave Xp11.3-p11.1 as the location of the A1S9T gene.
Combining these data with those of Zacksenhaus et al. (1989, 1990), one
might conclude that the location is Xp11.3-p11.2. By high-resolution
fluorescence in situ hybridization, Takahashi et al. (1991, 1992) mapped
the UBE1 gene to Xp11.3-p11.23.
EVOLUTION
Mitchell et al. (1991) and Kay et al. (1991) demonstrated homology of a
candidate spermatogenesis gene on the mouse Y chromosome to the UBE1
gene on the X chromosome. Mitchell et al. (1991) reported the isolation
of a new testis-specific gene, Sby, mapping to the DNA deleted from the
Sxr (sex-reversed) region in the mouse. It showed extensive homology to
UBE1. Because of its critical role in nuclear DNA replication, together
with the testis-specific expression, it was considered a candidate for
the spermatogenic gene Spy, which was known to be required for the
survival and proliferation of A spermatogonia during spermatogenesis.
Kay et al. (1991) isolated part of the mouse A1s9 gene, mapped it to the
proximal portion of the X chromosome, and showed that it undergoes
normal X-inactivation. They also detected 2 copies of the gene on the
short arm of the mouse Y chromosome, A1s9Y1 and A1s9Y2. They found that
A1s9Y1 is expressed in testis and is lost in the deletion form of Sxr.
A1s9X is similar to the Zfx gene (314980), which undergoes
X-inactivation, yet has homologous sequences on the short arm of the Y
chromosome that are expressed in the testis. These Y-linked genes may
form part of a coregulated group of genes which function during
spermatogenesis.
Mammalian sex chromosomes are thought to be descended from a homologous
pair of autosomes: a testis-determining allele which defined the Y
chromosome arose, recombination between the nascent X and Y chromosomes
became restricted, and the Y chromosome gradually lost its nonessential
genetic functions. This model was originally inferred from the
occurrence of a few Y-linked genetic traits, pairing of the X and Y
chromosomes during male meiosis, and the existence of X-Y homologous
genes. UBE1 is an X-linked gene with a distinct Y-linked homolog in many
eutherian (placental) and metatherian (marsupial) mammals. Nonetheless,
no UBE1 homolog is detectable on the human Y chromosome. Mitchell et al.
(1998) studied extensively the UBE1 homologs in primates and a
prototherian mammal, the platypus. Their findings indicated that UBE1
lies within the X-Y pairing segment of the platypus but is absent from
the human Y chromosome, having been lost from the Y chromosome during
evolution of the primate lineage.
MOLECULAR GENETICS
X-linked infantile spinal muscular atrophy (XLSMA), also known as
X-linked distal arthrogryposis multiplex congenita (301830), presents
with hypotonia, arreflexia, and multiple congenital contractures
associated with loss of anterior horn cells and infantile death. To
identify the XLSMA disease gene, Ramser et al. (2008) performed
large-scale mutation analysis in genes located between markers DXS8080
and DXS7132, the critical interval on Xp11.3-q11.1 indicated by linkage
studies. This resulted in detection of 3 rare novel variants in exon 15
of UBE1 that segregated with the disease: 2 missense mutations present
in each of 1 XLSMA family (314370.0001, 314370.0002), and 1 synonymous
C-to-T substitution (314370.0003) identified in another 3 unrelated
families. In a sixth family, neither of the 2 missense mutations or the
synonymous substitution was identified. Ramser et al. (2008)
demonstrated that the synonymous C-to-T substitution leads to
significant reduction of UBE1 expression and alters the methylation
pattern of exon 15, implying a plausible role of this DNA element in
developmental UBE1 expression in humans. Thus, XLSMA is one of several
neurodegenerative disorders associated with defects in the
ubiquitin-proteasome pathway. The authors concluded that their
experience indicated that synonymous C-to-T transitions have the
potential to affect gene expression.
*FIELD* AV
.0001
SPINAL MUSCULAR ATROPHY, X-LINKED 2
UBE1, MET539ILE
In a family with infantile X-linked spinal muscular atrophy (301830),
Ramser et al. (2008) detected a G-to-T transversion of nucleotide 1617
in exon 15 of the UBE1 gene that resulted in substitution of ile for met
at codon 539 (M539I).
.0002
SPINAL MUSCULAR ATROPHY, X-LINKED 2
UBE1, SER547GLY
In a family with infantile X-linked spinal muscular atrophy (301830),
Ramser et al. (2008) detected a A-to-G transition of nucleotide 1639 in
exon 15 of the UBE1 gene that resulted in substitution of gly for ser at
codon 547 (S547G).
.0003
SPINAL MUSCULAR ATROPHY, X-LINKED 2
UBE1, ASN577ASN
In 3 families with infantile X-linked spinal muscular atrophy (301830),
Ramser et al. (2008) detected a novel synonymous C-to-T transition at
nucleotide 1731 in exon 15 of the UBE1 gene. This substitution led to
significant reduction of UBE1 expression and alteration of the
methylation pattern of exon 15.
*FIELD* SA
Zacksenhaus and Sheinin (1990)
*FIELD* RF
1. Brown, C. J.; Powers, V. E.; Willard, H. F.: Localization of the
A1S9T gene to the proximal short arm of the X chromosome. (Abstract) Cytogenet.
Cell Genet. 51: 970 only, 1989.
2. Brown, C. J.; Willard, H. F.: Noninactivation of a selectable
human X-linked gene that complements a murine temperature-sensitive
cell cycle defect. Am. J. Hum. Genet. 45: 592-598, 1989.
3. Brown, C. J.; Willard, H. F.: Localization of a gene that escapes
inactivation to the X chromosome proximal short arm: implications
for X inactivation. Am. J. Hum. Genet. 46: 273-279, 1990.
4. Handley, P. M.; Mueckler, M.; Siegel, N. R.; Ciechanover, A.; Schwartz,
A. L.: Molecular cloning, sequence, and tissue distribution of the
human ubiquitin-activating enzyme E1. Proc. Nat. Acad. Sci. 88:
258-262, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 88: 7456 only,
1991.
5. Jin, J.; Li, X.; Gygi, S. P.; Harper, J. W.: Dual E1 activation
systems for ubiquitin differentially regulate E2 enzyme charging. Nature 447:
1135-1138, 2007.
6. Kay, G. F.; Ashworth, A.; Penny, G. D.; Dunlop, M.; Swift, S.;
Brockdorff, N.; Rastan, S.: A candidate spermatogenesis gene on the
mouse Y chromosome is homologous to ubiquitin-activation enzyme E1. Nature 354:
486-489, 1991.
7. Larola, G.; Cuesta, R.; Brewer, G.; Schneider, R. J.: Control
of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 284:
499-502, 1999.
8. Mitchell, M. J.; Wilcox, S. A.; Watson, J. M.; Lerner, J. L.; Woods,
D. R.; Scheffler, J.; Hearn, J. P.; Bishop, C. E.; Marshall Graves,
J. A.: The origin and loss of the ubiquitin activating enzyme gene
on the mammalian Y chromosome. Hum. Molec. Genet. 7: 429-434, 1998.
9. Mitchell, M. J.; Woods, D. R.; Tucker, P. K.; Opp, J. S.; Bishop,
C. E.: Homology of a candidate spermatogenic gene from the mouse
Y chromosome to the ubiquitin-activating enzyme E1. Nature 354:
483-486, 1991.
10. Nishimoto, T.; Basilico, C.: Analysis of a method for selecting
temperature-sensitive mutants of BHK cells. Somat. Cell Genet. 4:
323-340, 1978.
11. Nishimoto, T.; Sekiguchi, T.; Kai, R.; Yamashita, K.; Takahashi,
T.; Sekiguchi, M.: Large-scale selection and analysis of temperature-sensitive
mutants for cell reproduction from BHK cells. Somat. Cell Genet. 8:
811-812, 1982.
12. Ohtsubo, M.; Nishimoto, T.: The gene coding a ubiquitin-activating
enzyme may locate on X chromosome. Biochem. Biophys. Res. Commun. 153:
1173-1178, 1988.
13. Ramser, J.; Ahearn, M. E.; Lenski, C.; Yariz, K. O.; Hellebrand,
H.; von Rhein, M.; Clark, R. D.; Schmutzler, R. K.; Lichtner, P.;
Hoffman, E. P.; Meindl, A.; Baumbach-Reardon, L.: Rare missense and
synonymous variants in UBE1 are associated with X-linked infantile
spinal muscular atrophy. Am. J. Hum. Genet. 82: 188-193, 2008.
14. Takahashi, E.; Ayusawa, D.; Kaneda, S.; Itoh, Y.; Seno, T.; Hori,
T.: The human ubiquitin-activating enzyme E1 gene (UBE1) mapped to
band Xp11.3-p11.23 by fluorescence in situ hybridization. Cytogenet.
Cell Genet. 59: 268-269, 1992.
15. Takahashi, E.-I.; Yamauchi, M.; Ayusawa, D.; Kaneda, S.; Seno,
T.; Meuth, M.; Hori, T.-A.: Chromosome mappings of the human cytidine-5-prime-triphosphate
synthetase (CTPS) gene and the human ubiquitin-activating enzyme UBE1
gene by fluorescence in situ hybridization. (Abstract) Cytogenet.
Cell Genet. 58: 1864 only, 1991.
16. Willard, H. F.; Powers, V. E.; Munroe, D. L. G.; Brown, C. J.
: Identification of a gene on the short arm of the X chromosome that
complements a mouse temperature-sensitive defect in DNA synthesis.
(Abstract) Cytogenet. Cell Genet. 46: 716 only, 1987.
17. Zacksenhaus, E.; Sheinin, R.: Identification of human gene complementing
ts A1S9 mouse L-cell defect in DNA replication following DNA-mediated
gene transfer. Somat. Cell Molec. Genet. 14: 371-379, 1988.
18. Zacksenhaus, E.; Sheinin, R.: Molecular cloning, primary structure
and expression of the human X linked A1S9 gene cDNA which complements
the ts A1S9 mouse L cell defect in DNA. EMBO J. 9: 2923-2929, 1990.
19. Zacksenhaus, E.; Sheinin, R.: Molecular cloning of human A1S9
locus: an X-linked gene essential for progression through S phase
of the cell cycle. Somat. Cell Molec. Genet. 15: 545-553, 1989.
20. Zacksenhaus, E.; Sheinin, R.; Wang, H. S.: The human S phase
gene A1S9 is located at Xp11.23-11.4. (Abstract) Am. J. Hum. Genet. 45
(suppl.): A169 only, 1989.
21. Zacksenhaus, E.; Sheinin, R.; Wang, H. S.: Localization of the
human A1S9 gene complementing the ts A1S9 mouse L-cell defect in DNA
replication and cell cycle progression to Xp11.2-p11.4. Cytogenet.
Cell Genet. 53: 20-22, 1990.
*FIELD* CN
Victor A. McKusick - updated: 2/19/2008
Patricia A. Hartz - updated: 7/30/2007
Ada Hamosh - updated: 4/16/1999
Victor A. McKusick - updated: 4/23/1998
*FIELD* CD
Victor A. McKusick: 1/9/1989
*FIELD* ED
carol: 03/14/2013
mgross: 2/6/2012
alopez: 6/26/2008
alopez: 2/27/2008
terry: 2/19/2008
carol: 8/20/2007
terry: 7/30/2007
mgross: 3/14/2000
alopez: 4/16/1999
carol: 4/23/1998
terry: 4/14/1998
carol: 3/17/1994
mimadm: 2/28/1994
carol: 6/17/1993
carol: 5/27/1993
carol: 4/7/1993
supermim: 3/17/1992
*RECORD*
*FIELD* NO
314370
*FIELD* TI
*314370 UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 1; UBA1
;;UBIQUITIN-ACTIVATING ENZYME 1; UBE1;;
read moreBN75 TEMPERATURE SENSITIVITY COMPLEMENTING; GXP1
TEMPERATURE-SENSITIVE MUTATION, MOUSE, COMPLEMENTATION OF, INCLUDED;;
tsA1S9, INCLUDED;;
A1S9T, INCLUDED;;
A1S9, INCLUDED
*FIELD* TX
DESCRIPTION
Modification of proteins with ubiquitin (UBB; 191339) or ubiquitin-like
proteins controls many signaling networks and requires a ubiquitin
activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a
ubiquitin protein ligase (E3). UBA1 is an E1 enzyme that initiates the
activation and conjugation of ubiquitin-like proteins (Jin et al.,
2007).
CLONING
Zacksenhaus and Sheinin (1989) cloned the human A1S9 cDNA following
DNA-mediated gene transfer.
Handley et al. (1991) described the cloning and sequencing of the cDNA
for human E1, their term for the ubiquitin-activating enzyme catalyzing
the first step in ubiquitin conjugation. The cDNA recognized a single
3.5-kb E1 message that was ubiquitous among tissues and cell lines
studied. In vitro translation of the mRNA yielded a major product of
approximately 118 kD, which was immunoprecipitated by the antihuman E1
antibody used to identify the clone.
Jin et al. (2007) stated that the 1,058-amino acid UBE1 protein contains
an N-terminal adenylation domain with 2 ThiF-1 regions, a catalytic
cysteine domain, and a C-terminal ubiquitin-fold domain that functions
to recruit E2s. Database analysis detected variable UBE1 expression in
all human tissues and cell lines examined.
GENE STRUCTURE
The UBE1 gene comprises 27 exons, including an alternative first exon
designated 1a (Ramser et al., 2008). Translation begins in exon 2.
GENE FUNCTION
Jin et al. (2007) showed that UBE1 was able to transfer ubiquitin to a
wide range of E2 substrates.
Ohtsubo and Nishimoto (1988) studied 2 cell lines with a
temperature-sensitive (ts) defect in the S-phase of cell cycle. Two
lines failed to complement each other and therefore are presumed to have
the same defect as demonstrated in 1 of them: a ts defect in the
ubiquitin-activating enzyme. X-linkage was shown for one of the cell
lines by demonstration of cosegregation with HPRT in interspecies
somatic cell hybrids. The complicated nature of the genetic control of
cell growth reflected in ts mutants is indicated by the fact that 23
complementation groups have been identified by cell fusion analysis
using polyethylene glycol (Nishimoto and Basilico, 1978; Nishimoto et
al., 1982).
It turned out that the UBE1 locus is the same as that of the
temperature-sensitive gene called A1S9T. Willard et al. (1987) studied
the human gene that complements an X-linked mouse temperature-sensitive
defect in DNA synthesis; it is apparently different from the X-linked
factor represented by entry 313650 inasmuch as it was found to be
located on the short arm rather than on the long arm. The mouse mutant
tsA1S9 was characterized as a defect in DNA synthesis affecting
conversion of low molecular weight, newly synthesized DNA to mature
chromosomal DNA. In hybrid cells between normal human cells and mutant
mouse cells, it was found that the X chromosome and specifically the
short arm of the X chromosome complemented the defect. Brown et al.
(1989) and Brown and Willard (1989) found that a somatic hybrid cell
containing the region Xp21.1-p11.1 as its only X-chromosomal material
was able to survive at the nonpermissive temperature and thus must
contain the A1S9T gene. Since they had previously found that this gene
can be expressed from an inactive X chromosome (although not from the
Y), the new findings indicated that a second region of the human X
chromosome, in addition to the distal Xp22.3 location of other genes
that escape inactivation (MIC2, STS, XG), is also not subject to X
chromosome inactivation.
Zacksenhaus and Sheinin (1988) isolated a human gene complementing the
defect in a temperature-sensitive mouse L-cell line called ts A1S9. The
defect is in a gene required for nuclear DNA replication early in the S
phase of the cell cycle. DNA-mediated gene transfer (DMGT) was used and
the highly repetitive Alu family, which is present in at least 1 copy in
virtually every human gene, was used as a marker for the presence of the
human DNA in transfected mouse cells. Zacksenhaus and Sheinin (1988)
stated that this was the first demonstration of transfer of a human
S-phase gene. That the gene is X-linked was suggested by the fact that
both active and inactive human X chromosomes corrected the defect. The
authors quoted observations indicating that the tsA1S9 gene product is
not required for polydeoxyribonucleotide chain synthesis per se; thus,
the gene does not encode DNA polymerase alpha or DNA ligase. DNA
polymerase beta and gamma, as well as poly(ADP-ribose) polymerase, had
also been ruled out. Some evidence suggested that the temperature-labile
A1S9 protein may participate in DNA topoisomerase-2 activity.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich
elements in the 3-prime untranslated region. Rapid decay involves
AU-rich binding protein AUF1 (601324), which complexes with heat-shock
proteins HSC70 (600816) and HSP70 (see 140550), translation initiation
factor EIF4G (600495), and poly(A)-binding protein (604679). AU-rich
mRNA decay is associated with displacement of EIF4G from AUF1,
ubiquitination of AUF1, and degradation of AUF1 by proteasomes.
Induction of HSP70 by heat shock, downregulation of the
ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme
E1, all result in HSP70 sequestration of AUF1 in the
perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs
and AUF1 protein. These results link the rapid degradation of cytokine
mRNAs to the ubiquitin-proteasome pathway (Larola et al., 1999).
MAPPING
Using Southern blot and in situ hybridization, Zacksenhaus et al. (1989,
1990) mapped the A1S9 gene to Xp11.4-p11.2. On the basis of a study of
somatic cell hybrids with various deleted human X chromosomes, Brown and
Willard (1990) gave Xp11.3-p11.1 as the location of the A1S9T gene.
Combining these data with those of Zacksenhaus et al. (1989, 1990), one
might conclude that the location is Xp11.3-p11.2. By high-resolution
fluorescence in situ hybridization, Takahashi et al. (1991, 1992) mapped
the UBE1 gene to Xp11.3-p11.23.
EVOLUTION
Mitchell et al. (1991) and Kay et al. (1991) demonstrated homology of a
candidate spermatogenesis gene on the mouse Y chromosome to the UBE1
gene on the X chromosome. Mitchell et al. (1991) reported the isolation
of a new testis-specific gene, Sby, mapping to the DNA deleted from the
Sxr (sex-reversed) region in the mouse. It showed extensive homology to
UBE1. Because of its critical role in nuclear DNA replication, together
with the testis-specific expression, it was considered a candidate for
the spermatogenic gene Spy, which was known to be required for the
survival and proliferation of A spermatogonia during spermatogenesis.
Kay et al. (1991) isolated part of the mouse A1s9 gene, mapped it to the
proximal portion of the X chromosome, and showed that it undergoes
normal X-inactivation. They also detected 2 copies of the gene on the
short arm of the mouse Y chromosome, A1s9Y1 and A1s9Y2. They found that
A1s9Y1 is expressed in testis and is lost in the deletion form of Sxr.
A1s9X is similar to the Zfx gene (314980), which undergoes
X-inactivation, yet has homologous sequences on the short arm of the Y
chromosome that are expressed in the testis. These Y-linked genes may
form part of a coregulated group of genes which function during
spermatogenesis.
Mammalian sex chromosomes are thought to be descended from a homologous
pair of autosomes: a testis-determining allele which defined the Y
chromosome arose, recombination between the nascent X and Y chromosomes
became restricted, and the Y chromosome gradually lost its nonessential
genetic functions. This model was originally inferred from the
occurrence of a few Y-linked genetic traits, pairing of the X and Y
chromosomes during male meiosis, and the existence of X-Y homologous
genes. UBE1 is an X-linked gene with a distinct Y-linked homolog in many
eutherian (placental) and metatherian (marsupial) mammals. Nonetheless,
no UBE1 homolog is detectable on the human Y chromosome. Mitchell et al.
(1998) studied extensively the UBE1 homologs in primates and a
prototherian mammal, the platypus. Their findings indicated that UBE1
lies within the X-Y pairing segment of the platypus but is absent from
the human Y chromosome, having been lost from the Y chromosome during
evolution of the primate lineage.
MOLECULAR GENETICS
X-linked infantile spinal muscular atrophy (XLSMA), also known as
X-linked distal arthrogryposis multiplex congenita (301830), presents
with hypotonia, arreflexia, and multiple congenital contractures
associated with loss of anterior horn cells and infantile death. To
identify the XLSMA disease gene, Ramser et al. (2008) performed
large-scale mutation analysis in genes located between markers DXS8080
and DXS7132, the critical interval on Xp11.3-q11.1 indicated by linkage
studies. This resulted in detection of 3 rare novel variants in exon 15
of UBE1 that segregated with the disease: 2 missense mutations present
in each of 1 XLSMA family (314370.0001, 314370.0002), and 1 synonymous
C-to-T substitution (314370.0003) identified in another 3 unrelated
families. In a sixth family, neither of the 2 missense mutations or the
synonymous substitution was identified. Ramser et al. (2008)
demonstrated that the synonymous C-to-T substitution leads to
significant reduction of UBE1 expression and alters the methylation
pattern of exon 15, implying a plausible role of this DNA element in
developmental UBE1 expression in humans. Thus, XLSMA is one of several
neurodegenerative disorders associated with defects in the
ubiquitin-proteasome pathway. The authors concluded that their
experience indicated that synonymous C-to-T transitions have the
potential to affect gene expression.
*FIELD* AV
.0001
SPINAL MUSCULAR ATROPHY, X-LINKED 2
UBE1, MET539ILE
In a family with infantile X-linked spinal muscular atrophy (301830),
Ramser et al. (2008) detected a G-to-T transversion of nucleotide 1617
in exon 15 of the UBE1 gene that resulted in substitution of ile for met
at codon 539 (M539I).
.0002
SPINAL MUSCULAR ATROPHY, X-LINKED 2
UBE1, SER547GLY
In a family with infantile X-linked spinal muscular atrophy (301830),
Ramser et al. (2008) detected a A-to-G transition of nucleotide 1639 in
exon 15 of the UBE1 gene that resulted in substitution of gly for ser at
codon 547 (S547G).
.0003
SPINAL MUSCULAR ATROPHY, X-LINKED 2
UBE1, ASN577ASN
In 3 families with infantile X-linked spinal muscular atrophy (301830),
Ramser et al. (2008) detected a novel synonymous C-to-T transition at
nucleotide 1731 in exon 15 of the UBE1 gene. This substitution led to
significant reduction of UBE1 expression and alteration of the
methylation pattern of exon 15.
*FIELD* SA
Zacksenhaus and Sheinin (1990)
*FIELD* RF
1. Brown, C. J.; Powers, V. E.; Willard, H. F.: Localization of the
A1S9T gene to the proximal short arm of the X chromosome. (Abstract) Cytogenet.
Cell Genet. 51: 970 only, 1989.
2. Brown, C. J.; Willard, H. F.: Noninactivation of a selectable
human X-linked gene that complements a murine temperature-sensitive
cell cycle defect. Am. J. Hum. Genet. 45: 592-598, 1989.
3. Brown, C. J.; Willard, H. F.: Localization of a gene that escapes
inactivation to the X chromosome proximal short arm: implications
for X inactivation. Am. J. Hum. Genet. 46: 273-279, 1990.
4. Handley, P. M.; Mueckler, M.; Siegel, N. R.; Ciechanover, A.; Schwartz,
A. L.: Molecular cloning, sequence, and tissue distribution of the
human ubiquitin-activating enzyme E1. Proc. Nat. Acad. Sci. 88:
258-262, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 88: 7456 only,
1991.
5. Jin, J.; Li, X.; Gygi, S. P.; Harper, J. W.: Dual E1 activation
systems for ubiquitin differentially regulate E2 enzyme charging. Nature 447:
1135-1138, 2007.
6. Kay, G. F.; Ashworth, A.; Penny, G. D.; Dunlop, M.; Swift, S.;
Brockdorff, N.; Rastan, S.: A candidate spermatogenesis gene on the
mouse Y chromosome is homologous to ubiquitin-activation enzyme E1. Nature 354:
486-489, 1991.
7. Larola, G.; Cuesta, R.; Brewer, G.; Schneider, R. J.: Control
of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 284:
499-502, 1999.
8. Mitchell, M. J.; Wilcox, S. A.; Watson, J. M.; Lerner, J. L.; Woods,
D. R.; Scheffler, J.; Hearn, J. P.; Bishop, C. E.; Marshall Graves,
J. A.: The origin and loss of the ubiquitin activating enzyme gene
on the mammalian Y chromosome. Hum. Molec. Genet. 7: 429-434, 1998.
9. Mitchell, M. J.; Woods, D. R.; Tucker, P. K.; Opp, J. S.; Bishop,
C. E.: Homology of a candidate spermatogenic gene from the mouse
Y chromosome to the ubiquitin-activating enzyme E1. Nature 354:
483-486, 1991.
10. Nishimoto, T.; Basilico, C.: Analysis of a method for selecting
temperature-sensitive mutants of BHK cells. Somat. Cell Genet. 4:
323-340, 1978.
11. Nishimoto, T.; Sekiguchi, T.; Kai, R.; Yamashita, K.; Takahashi,
T.; Sekiguchi, M.: Large-scale selection and analysis of temperature-sensitive
mutants for cell reproduction from BHK cells. Somat. Cell Genet. 8:
811-812, 1982.
12. Ohtsubo, M.; Nishimoto, T.: The gene coding a ubiquitin-activating
enzyme may locate on X chromosome. Biochem. Biophys. Res. Commun. 153:
1173-1178, 1988.
13. Ramser, J.; Ahearn, M. E.; Lenski, C.; Yariz, K. O.; Hellebrand,
H.; von Rhein, M.; Clark, R. D.; Schmutzler, R. K.; Lichtner, P.;
Hoffman, E. P.; Meindl, A.; Baumbach-Reardon, L.: Rare missense and
synonymous variants in UBE1 are associated with X-linked infantile
spinal muscular atrophy. Am. J. Hum. Genet. 82: 188-193, 2008.
14. Takahashi, E.; Ayusawa, D.; Kaneda, S.; Itoh, Y.; Seno, T.; Hori,
T.: The human ubiquitin-activating enzyme E1 gene (UBE1) mapped to
band Xp11.3-p11.23 by fluorescence in situ hybridization. Cytogenet.
Cell Genet. 59: 268-269, 1992.
15. Takahashi, E.-I.; Yamauchi, M.; Ayusawa, D.; Kaneda, S.; Seno,
T.; Meuth, M.; Hori, T.-A.: Chromosome mappings of the human cytidine-5-prime-triphosphate
synthetase (CTPS) gene and the human ubiquitin-activating enzyme UBE1
gene by fluorescence in situ hybridization. (Abstract) Cytogenet.
Cell Genet. 58: 1864 only, 1991.
16. Willard, H. F.; Powers, V. E.; Munroe, D. L. G.; Brown, C. J.
: Identification of a gene on the short arm of the X chromosome that
complements a mouse temperature-sensitive defect in DNA synthesis.
(Abstract) Cytogenet. Cell Genet. 46: 716 only, 1987.
17. Zacksenhaus, E.; Sheinin, R.: Identification of human gene complementing
ts A1S9 mouse L-cell defect in DNA replication following DNA-mediated
gene transfer. Somat. Cell Molec. Genet. 14: 371-379, 1988.
18. Zacksenhaus, E.; Sheinin, R.: Molecular cloning, primary structure
and expression of the human X linked A1S9 gene cDNA which complements
the ts A1S9 mouse L cell defect in DNA. EMBO J. 9: 2923-2929, 1990.
19. Zacksenhaus, E.; Sheinin, R.: Molecular cloning of human A1S9
locus: an X-linked gene essential for progression through S phase
of the cell cycle. Somat. Cell Molec. Genet. 15: 545-553, 1989.
20. Zacksenhaus, E.; Sheinin, R.; Wang, H. S.: The human S phase
gene A1S9 is located at Xp11.23-11.4. (Abstract) Am. J. Hum. Genet. 45
(suppl.): A169 only, 1989.
21. Zacksenhaus, E.; Sheinin, R.; Wang, H. S.: Localization of the
human A1S9 gene complementing the ts A1S9 mouse L-cell defect in DNA
replication and cell cycle progression to Xp11.2-p11.4. Cytogenet.
Cell Genet. 53: 20-22, 1990.
*FIELD* CN
Victor A. McKusick - updated: 2/19/2008
Patricia A. Hartz - updated: 7/30/2007
Ada Hamosh - updated: 4/16/1999
Victor A. McKusick - updated: 4/23/1998
*FIELD* CD
Victor A. McKusick: 1/9/1989
*FIELD* ED
carol: 03/14/2013
mgross: 2/6/2012
alopez: 6/26/2008
alopez: 2/27/2008
terry: 2/19/2008
carol: 8/20/2007
terry: 7/30/2007
mgross: 3/14/2000
alopez: 4/16/1999
carol: 4/23/1998
terry: 4/14/1998
carol: 3/17/1994
mimadm: 2/28/1994
carol: 6/17/1993
carol: 5/27/1993
carol: 4/7/1993
supermim: 3/17/1992