Full text data of UBQLN2
UBQLN2
(N4BP4, PLIC2)
[Confidence: low (only semi-automatic identification from reviews)]
Ubiquilin-2 (Chap1; DSK2 homolog; Protein linking IAP with cytoskeleton 2; PLIC-2; hPLIC-2; Ubiquitin-like product Chap1/Dsk2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ubiquilin-2 (Chap1; DSK2 homolog; Protein linking IAP with cytoskeleton 2; PLIC-2; hPLIC-2; Ubiquitin-like product Chap1/Dsk2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9UHD9
ID UBQL2_HUMAN Reviewed; 624 AA.
AC Q9UHD9; O94798; Q5D027; Q9H3W6; Q9HAZ4;
DT 29-MAR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 114.
DE RecName: Full=Ubiquilin-2;
DE AltName: Full=Chap1;
DE AltName: Full=DSK2 homolog;
DE AltName: Full=Protein linking IAP with cytoskeleton 2;
DE Short=PLIC-2;
DE Short=hPLIC-2;
DE AltName: Full=Ubiquitin-like product Chap1/Dsk2;
GN Name=UBQLN2; Synonyms=N4BP4, PLIC2; ORFNames=HRIHFB2157;
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], AND INTERACTION WITH STCH.
RC TISSUE=Lung;
RX PubMed=10675567; DOI=10.1016/S0014-5793(00)01135-2;
RA Kaye F.J., Modi S., Ivanovska I., Koonin E.V., Thress K., Kubo A.,
RA Kornbluth S., Rose M.D.;
RT "A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-
RT like Stch.";
RL FEBS Lett. 467:348-355(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH THE PROTEASOME AND UBE3A.
RC TISSUE=B-cell;
RX PubMed=10983987; DOI=10.1016/S1097-2765(00)00040-X;
RA Kleijnen M.F., Shih A.H., Zhou P., Kumar S., Soccio R.E.,
RA Kedersha N.L., Gill G., Howley P.M.;
RT "The hPLIC proteins may provide a link between the ubiquitination
RT machinery and the proteasome.";
RL Mol. Cell 6:409-419(2000).
RN [3]
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 37-624.
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 217-624, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Fetal brain;
RX PubMed=9853615; DOI=10.1038/4315;
RA Ueki N., Oda T., Kondo M., Yano K., Noguchi T., Muramatsu M.-A.;
RT "Selection system for genes encoding nuclear-targeted proteins.";
RL Nat. Biotechnol. 16:1338-1342(1998).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [9]
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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
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 [11]
RP STRUCTURE BY NMR OF 1-103.
RX PubMed=11827521; DOI=10.1021/bi011892y;
RA Walters K.J., Kleijnen M.F., Goh A.M., Wagner G., Howley P.M.;
RT "Structural studies of the interaction between ubiquitin family
RT proteins and proteasome subunit S5a.";
RL Biochemistry 41:1767-1777(2002).
RN [12]
RP VARIANTS ALS15 HIS-497; SER-497; THR-506; SER-509 AND SER-525, AND
RP CHARACTERIZATION OF VARIANTS ALS15 HIS-497 AND THR-506.
RX PubMed=21857683; DOI=10.1038/nature10353;
RA Deng H.X., Chen W., Hong S.T., Boycott K.M., Gorrie G.H., Siddique N.,
RA Yang Y., Fecto F., Shi Y., Zhai H., Jiang H., Hirano M.,
RA Rampersaud E., Jansen G.H., Donkervoort S., Bigio E.H., Brooks B.R.,
RA Ajroud K., Sufit R.L., Haines J.L., Mugnaini E., Pericak-Vance M.A.,
RA Siddique T.;
RT "Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset
RT ALS and ALS/dementia.";
RL Nature 477:211-215(2011).
RN [13]
RP VARIANTS ALS15 THR-283 AND ARG-425, AND VARIANT VAL-282.
RX PubMed=22892309; DOI=10.1016/j.neurobiolaging.2012.07.002;
RA Synofzik M., Maetzler W., Grehl T., Prudlo J., Vom Hagen J.M.,
RA Haack T., Rebassoo P., Munz M., Schols L., Biskup S.;
RT "Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations
RT outside the PXX domain and a pure FTD phenotype.";
RL Neurobiol. Aging 33:E13-E17(2012).
RN [14]
RP VARIANT ALS15 ILE-487.
RX PubMed=22717235; DOI=10.1016/j.neurobiolaging.2012.05.008;
RA Williams K.L., Warraich S.T., Yang S., Solski J.A., Fernando R.,
RA Rouleau G.A., Nicholson G.A., Blair I.P.;
RT "UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic
RT lateral sclerosis.";
RL Neurobiol. Aging 33:E3-E10(2012).
RN [15]
RP VARIANTS ALS15 ASN-155 AND THR-189.
RX PubMed=22560112; DOI=10.1016/j.neurobiolaging.2012.03.015;
RA Daoud H., Suhail H., Szuto A., Camu W., Salachas F., Meininger V.,
RA Bouchard J.P., Dupre N., Dion P.A., Rouleau G.A.;
RT "UBQLN2 mutations are rare in French and French-Canadian amyotrophic
RT lateral sclerosis.";
RL Neurobiol. Aging 33:E1-E5(2012).
CC -!- FUNCTION: Increases the half-life of proteins destined to be
CC degraded by the proteasome; may modulate proteasome-mediated
CC protein degradation.
CC -!- SUBUNIT: Binds UBE3A and BTRC. Interacts with the 19S proteasome
CC subunit.
CC -!- INTERACTION:
CC Q16186:ADRM1; NbExp=3; IntAct=EBI-947187, EBI-954387;
CC P55036:PSMD4; NbExp=3; IntAct=EBI-947187, EBI-359318;
CC P54725:RAD23A; NbExp=3; IntAct=EBI-947187, EBI-746453;
CC O48726:RPN13 (xeno); NbExp=4; IntAct=EBI-947187, EBI-7710745;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Where it
CC colocalizes with the proteasome. Associated with fibers in mitotic
CC cells.
CC -!- INDUCTION: Highly expressed in mitotic cells from metaphase to
CC telophase. Expression in non-mitotic cells is very low.
CC -!- DISEASE: Amyotrophic lateral sclerosis 15, with or without
CC frontotemporal dementia (ALS15) [MIM:300857]: A neurodegenerative
CC disorder affecting upper motor neurons in the brain and lower
CC motor neurons in the brain stem and spinal cord, resulting in
CC fatal paralysis. Sensory abnormalities are absent. The pathologic
CC hallmarks of the disease include pallor of the corticospinal tract
CC due to loss of motor neurons, presence of ubiquitin-positive
CC inclusions within surviving motor neurons, and deposition of
CC pathologic aggregates. The etiology of amyotrophic lateral
CC sclerosis is likely to be multifactorial, involving both genetic
CC and environmental factors. The disease is inherited in 5-10% of
CC the cases. Patients with ALS15 may develop frontotemporal
CC dementia. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 1 UBA domain.
CC -!- SIMILARITY: Contains 1 ubiquitin-like domain.
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; AF189009; AAF17237.1; -; mRNA.
DR EMBL; AF293385; AAG02474.1; -; mRNA.
DR EMBL; AL354793; CAD13519.1; -; Genomic_DNA.
DR EMBL; CH471154; EAW93233.1; -; Genomic_DNA.
DR EMBL; BC069237; AAH69237.1; -; mRNA.
DR EMBL; AL442081; CAC09446.1; -; mRNA.
DR EMBL; AB015344; BAA34801.1; -; mRNA.
DR RefSeq; NP_038472.2; NM_013444.3.
DR UniGene; Hs.179309; -.
DR PDB; 1J8C; NMR; -; A=1-103.
DR PDBsum; 1J8C; -.
DR ProteinModelPortal; Q9UHD9; -.
DR SMR; Q9UHD9; 1-103, 578-624.
DR DIP; DIP-42116N; -.
DR IntAct; Q9UHD9; 12.
DR MINT; MINT-1192483; -.
DR STRING; 9606.ENSP00000345195; -.
DR PhosphoSite; Q9UHD9; -.
DR DMDM; 124056593; -.
DR PaxDb; Q9UHD9; -.
DR PeptideAtlas; Q9UHD9; -.
DR PRIDE; Q9UHD9; -.
DR Ensembl; ENST00000338222; ENSP00000345195; ENSG00000188021.
DR GeneID; 29978; -.
DR KEGG; hsa:29978; -.
DR UCSC; uc004dus.3; human.
DR CTD; 29978; -.
DR GeneCards; GC0XP056606; -.
DR HGNC; HGNC:12509; UBQLN2.
DR HPA; CAB013481; -.
DR HPA; HPA006431; -.
DR MIM; 300264; gene.
DR MIM; 300857; phenotype.
DR neXtProt; NX_Q9UHD9; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA37156; -.
DR eggNOG; COG5272; -.
DR HOGENOM; HOG000234878; -.
DR HOVERGEN; HBG064537; -.
DR InParanoid; Q9UHD9; -.
DR KO; K04523; -.
DR OMA; LMASPEM; -.
DR OrthoDB; EOG7HF1J8; -.
DR PhylomeDB; Q9UHD9; -.
DR EvolutionaryTrace; Q9UHD9; -.
DR GeneWiki; UBQLN2; -.
DR GenomeRNAi; 29978; -.
DR NextBio; 52728; -.
DR PRO; PR:Q9UHD9; -.
DR Bgee; Q9UHD9; -.
DR CleanEx; HS_UBQLN2; -.
DR Genevestigator; Q9UHD9; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR006636; STI1_HS-bd.
DR InterPro; IPR009060; UBA-like.
DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk.
DR InterPro; IPR000449; UBA/Ts_N.
DR InterPro; IPR015496; Ubiquilin.
DR InterPro; IPR028430; Ubiquilin-2.
DR InterPro; IPR000626; Ubiquitin_dom.
DR PANTHER; PTHR10677; PTHR10677; 1.
DR PANTHER; PTHR10677:SF5; PTHR10677:SF5; 1.
DR Pfam; PF00627; UBA; 1.
DR Pfam; PF00240; ubiquitin; 1.
DR SMART; SM00727; STI1; 4.
DR SMART; SM00165; UBA; 1.
DR SMART; SM00213; UBQ; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS50030; UBA; 1.
DR PROSITE; PS00299; UBIQUITIN_1; FALSE_NEG.
DR PROSITE; PS50053; UBIQUITIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis;
KW Complete proteome; Cytoplasm; Disease mutation; Neurodegeneration;
KW Nucleus; Polymorphism; Reference proteome; Repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 624 Ubiquilin-2.
FT /FTId=PRO_0000211011.
FT DOMAIN 33 107 Ubiquitin-like.
FT REPEAT 491 493 1.
FT REPEAT 494 496 2.
FT REPEAT 497 499 3.
FT REPEAT 500 502 4.
FT REPEAT 503 505 5.
FT REPEAT 506 508 6.
FT REPEAT 509 511 7.
FT REPEAT 512 514 8.
FT REPEAT 515 517 9.
FT REPEAT 518 520 10.
FT REPEAT 521 523 11.
FT REPEAT 524 526 12.
FT DOMAIN 581 621 UBA.
FT REGION 491 526 12 X 3 AA tandem repeats of P-X-X.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 155 155 S -> N (in ALS15; uncertain pathological
FT significance).
FT /FTId=VAR_068892.
FT VARIANT 189 189 P -> T (in ALS15; uncertain pathological
FT significance).
FT /FTId=VAR_068893.
FT VARIANT 235 235 L -> H (in dbSNP:rs17002693).
FT /FTId=VAR_052680.
FT VARIANT 282 282 A -> V (probable disease-associated
FT mutation found in a patient with
FT frontotemporal dementia).
FT /FTId=VAR_068894.
FT VARIANT 283 283 A -> T (in ALS15).
FT /FTId=VAR_068895.
FT VARIANT 425 425 Q -> R (in ALS15).
FT /FTId=VAR_068896.
FT VARIANT 487 487 T -> I (in ALS15).
FT /FTId=VAR_068897.
FT VARIANT 497 497 P -> H (in ALS15; leads to defective
FT ubiquitin-mediated proteasomal
FT degradation).
FT /FTId=VAR_066562.
FT VARIANT 497 497 P -> S (in ALS15).
FT /FTId=VAR_066563.
FT VARIANT 506 506 P -> T (in ALS15; leads to defective
FT ubiquitin-mediated proteasomal
FT degradation).
FT /FTId=VAR_066564.
FT VARIANT 509 509 P -> S (in ALS15).
FT /FTId=VAR_066565.
FT VARIANT 525 525 P -> S (in ALS15).
FT /FTId=VAR_066566.
FT CONFLICT 544 544 S -> R (in Ref. 1 and 5).
FT STRAND 23 25
FT STRAND 33 38
FT STRAND 43 48
FT HELIX 54 65
FT STRAND 69 76
FT STRAND 79 82
FT HELIX 87 91
FT STRAND 93 102
SQ SEQUENCE 624 AA; 65696 MW; DF7DF8C4D7B71AC3 CRC64;
MAENGESSGP PRPSRGPAAA QGSAAAPAEP KIIKVTVKTP KEKEEFAVPE NSSVQQFKEA
ISKRFKSQTD QLVLIFAGKI LKDQDTLIQH GIHDGLTVHL VIKSQNRPQG QSTQPSNAAG
TNTTSASTPR SNSTPISTNS NPFGLGSLGG LAGLSSLGLS STNFSELQSQ MQQQLMASPE
MMIQIMENPF VQSMLSNPDL MRQLIMANPQ MQQLIQRNPE ISHLLNNPDI MRQTLEIARN
PAMMQEMMRN QDLALSNLES IPGGYNALRR MYTDIQEPML NAAQEQFGGN PFASVGSSSS
SGEGTQPSRT ENRDPLPNPW APPPATQSSA TTSTTTSTGS GSGNSSSNAT GNTVAAANYV
ASIFSTPGMQ SLLQQITENP QLIQNMLSAP YMRSMMQSLS QNPDLAAQMM LNSPLFTANP
QLQEQMRPQL PAFLQQMQNP DTLSAMSNPR AMQALMQIQQ GLQTLATEAP GLIPSFTPGV
GVGVLGTAIG PVGPVTPIGP IGPIVPFTPI GPIGPIGPTG PAAPPGSTGS GGPTGPTVSS
AAPSETTSPT SESGPNQQFI QQMVQALAGA NAPQLPNPEV RFQQQLEQLN AMGFLNREAN
LQALIATGGD INAAIERLLG SQPS
//
ID UBQL2_HUMAN Reviewed; 624 AA.
AC Q9UHD9; O94798; Q5D027; Q9H3W6; Q9HAZ4;
DT 29-MAR-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 114.
DE RecName: Full=Ubiquilin-2;
DE AltName: Full=Chap1;
DE AltName: Full=DSK2 homolog;
DE AltName: Full=Protein linking IAP with cytoskeleton 2;
DE Short=PLIC-2;
DE Short=hPLIC-2;
DE AltName: Full=Ubiquitin-like product Chap1/Dsk2;
GN Name=UBQLN2; Synonyms=N4BP4, PLIC2; ORFNames=HRIHFB2157;
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], AND INTERACTION WITH STCH.
RC TISSUE=Lung;
RX PubMed=10675567; DOI=10.1016/S0014-5793(00)01135-2;
RA Kaye F.J., Modi S., Ivanovska I., Koonin E.V., Thress K., Kubo A.,
RA Kornbluth S., Rose M.D.;
RT "A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-
RT like Stch.";
RL FEBS Lett. 467:348-355(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH THE PROTEASOME AND UBE3A.
RC TISSUE=B-cell;
RX PubMed=10983987; DOI=10.1016/S1097-2765(00)00040-X;
RA Kleijnen M.F., Shih A.H., Zhou P., Kumar S., Soccio R.E.,
RA Kedersha N.L., Gill G., Howley P.M.;
RT "The hPLIC proteins may provide a link between the ubiquitination
RT machinery and the proteasome.";
RL Mol. Cell 6:409-419(2000).
RN [3]
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 37-624.
RC TISSUE=Amygdala;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 217-624, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Fetal brain;
RX PubMed=9853615; DOI=10.1038/4315;
RA Ueki N., Oda T., Kondo M., Yano K., Noguchi T., Muramatsu M.-A.;
RT "Selection system for genes encoding nuclear-targeted proteins.";
RL Nat. Biotechnol. 16:1338-1342(1998).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [9]
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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
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 [11]
RP STRUCTURE BY NMR OF 1-103.
RX PubMed=11827521; DOI=10.1021/bi011892y;
RA Walters K.J., Kleijnen M.F., Goh A.M., Wagner G., Howley P.M.;
RT "Structural studies of the interaction between ubiquitin family
RT proteins and proteasome subunit S5a.";
RL Biochemistry 41:1767-1777(2002).
RN [12]
RP VARIANTS ALS15 HIS-497; SER-497; THR-506; SER-509 AND SER-525, AND
RP CHARACTERIZATION OF VARIANTS ALS15 HIS-497 AND THR-506.
RX PubMed=21857683; DOI=10.1038/nature10353;
RA Deng H.X., Chen W., Hong S.T., Boycott K.M., Gorrie G.H., Siddique N.,
RA Yang Y., Fecto F., Shi Y., Zhai H., Jiang H., Hirano M.,
RA Rampersaud E., Jansen G.H., Donkervoort S., Bigio E.H., Brooks B.R.,
RA Ajroud K., Sufit R.L., Haines J.L., Mugnaini E., Pericak-Vance M.A.,
RA Siddique T.;
RT "Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset
RT ALS and ALS/dementia.";
RL Nature 477:211-215(2011).
RN [13]
RP VARIANTS ALS15 THR-283 AND ARG-425, AND VARIANT VAL-282.
RX PubMed=22892309; DOI=10.1016/j.neurobiolaging.2012.07.002;
RA Synofzik M., Maetzler W., Grehl T., Prudlo J., Vom Hagen J.M.,
RA Haack T., Rebassoo P., Munz M., Schols L., Biskup S.;
RT "Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations
RT outside the PXX domain and a pure FTD phenotype.";
RL Neurobiol. Aging 33:E13-E17(2012).
RN [14]
RP VARIANT ALS15 ILE-487.
RX PubMed=22717235; DOI=10.1016/j.neurobiolaging.2012.05.008;
RA Williams K.L., Warraich S.T., Yang S., Solski J.A., Fernando R.,
RA Rouleau G.A., Nicholson G.A., Blair I.P.;
RT "UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic
RT lateral sclerosis.";
RL Neurobiol. Aging 33:E3-E10(2012).
RN [15]
RP VARIANTS ALS15 ASN-155 AND THR-189.
RX PubMed=22560112; DOI=10.1016/j.neurobiolaging.2012.03.015;
RA Daoud H., Suhail H., Szuto A., Camu W., Salachas F., Meininger V.,
RA Bouchard J.P., Dupre N., Dion P.A., Rouleau G.A.;
RT "UBQLN2 mutations are rare in French and French-Canadian amyotrophic
RT lateral sclerosis.";
RL Neurobiol. Aging 33:E1-E5(2012).
CC -!- FUNCTION: Increases the half-life of proteins destined to be
CC degraded by the proteasome; may modulate proteasome-mediated
CC protein degradation.
CC -!- SUBUNIT: Binds UBE3A and BTRC. Interacts with the 19S proteasome
CC subunit.
CC -!- INTERACTION:
CC Q16186:ADRM1; NbExp=3; IntAct=EBI-947187, EBI-954387;
CC P55036:PSMD4; NbExp=3; IntAct=EBI-947187, EBI-359318;
CC P54725:RAD23A; NbExp=3; IntAct=EBI-947187, EBI-746453;
CC O48726:RPN13 (xeno); NbExp=4; IntAct=EBI-947187, EBI-7710745;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Where it
CC colocalizes with the proteasome. Associated with fibers in mitotic
CC cells.
CC -!- INDUCTION: Highly expressed in mitotic cells from metaphase to
CC telophase. Expression in non-mitotic cells is very low.
CC -!- DISEASE: Amyotrophic lateral sclerosis 15, with or without
CC frontotemporal dementia (ALS15) [MIM:300857]: A neurodegenerative
CC disorder affecting upper motor neurons in the brain and lower
CC motor neurons in the brain stem and spinal cord, resulting in
CC fatal paralysis. Sensory abnormalities are absent. The pathologic
CC hallmarks of the disease include pallor of the corticospinal tract
CC due to loss of motor neurons, presence of ubiquitin-positive
CC inclusions within surviving motor neurons, and deposition of
CC pathologic aggregates. The etiology of amyotrophic lateral
CC sclerosis is likely to be multifactorial, involving both genetic
CC and environmental factors. The disease is inherited in 5-10% of
CC the cases. Patients with ALS15 may develop frontotemporal
CC dementia. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 1 UBA domain.
CC -!- SIMILARITY: Contains 1 ubiquitin-like domain.
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; AF189009; AAF17237.1; -; mRNA.
DR EMBL; AF293385; AAG02474.1; -; mRNA.
DR EMBL; AL354793; CAD13519.1; -; Genomic_DNA.
DR EMBL; CH471154; EAW93233.1; -; Genomic_DNA.
DR EMBL; BC069237; AAH69237.1; -; mRNA.
DR EMBL; AL442081; CAC09446.1; -; mRNA.
DR EMBL; AB015344; BAA34801.1; -; mRNA.
DR RefSeq; NP_038472.2; NM_013444.3.
DR UniGene; Hs.179309; -.
DR PDB; 1J8C; NMR; -; A=1-103.
DR PDBsum; 1J8C; -.
DR ProteinModelPortal; Q9UHD9; -.
DR SMR; Q9UHD9; 1-103, 578-624.
DR DIP; DIP-42116N; -.
DR IntAct; Q9UHD9; 12.
DR MINT; MINT-1192483; -.
DR STRING; 9606.ENSP00000345195; -.
DR PhosphoSite; Q9UHD9; -.
DR DMDM; 124056593; -.
DR PaxDb; Q9UHD9; -.
DR PeptideAtlas; Q9UHD9; -.
DR PRIDE; Q9UHD9; -.
DR Ensembl; ENST00000338222; ENSP00000345195; ENSG00000188021.
DR GeneID; 29978; -.
DR KEGG; hsa:29978; -.
DR UCSC; uc004dus.3; human.
DR CTD; 29978; -.
DR GeneCards; GC0XP056606; -.
DR HGNC; HGNC:12509; UBQLN2.
DR HPA; CAB013481; -.
DR HPA; HPA006431; -.
DR MIM; 300264; gene.
DR MIM; 300857; phenotype.
DR neXtProt; NX_Q9UHD9; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA37156; -.
DR eggNOG; COG5272; -.
DR HOGENOM; HOG000234878; -.
DR HOVERGEN; HBG064537; -.
DR InParanoid; Q9UHD9; -.
DR KO; K04523; -.
DR OMA; LMASPEM; -.
DR OrthoDB; EOG7HF1J8; -.
DR PhylomeDB; Q9UHD9; -.
DR EvolutionaryTrace; Q9UHD9; -.
DR GeneWiki; UBQLN2; -.
DR GenomeRNAi; 29978; -.
DR NextBio; 52728; -.
DR PRO; PR:Q9UHD9; -.
DR Bgee; Q9UHD9; -.
DR CleanEx; HS_UBQLN2; -.
DR Genevestigator; Q9UHD9; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR006636; STI1_HS-bd.
DR InterPro; IPR009060; UBA-like.
DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk.
DR InterPro; IPR000449; UBA/Ts_N.
DR InterPro; IPR015496; Ubiquilin.
DR InterPro; IPR028430; Ubiquilin-2.
DR InterPro; IPR000626; Ubiquitin_dom.
DR PANTHER; PTHR10677; PTHR10677; 1.
DR PANTHER; PTHR10677:SF5; PTHR10677:SF5; 1.
DR Pfam; PF00627; UBA; 1.
DR Pfam; PF00240; ubiquitin; 1.
DR SMART; SM00727; STI1; 4.
DR SMART; SM00165; UBA; 1.
DR SMART; SM00213; UBQ; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR PROSITE; PS50030; UBA; 1.
DR PROSITE; PS00299; UBIQUITIN_1; FALSE_NEG.
DR PROSITE; PS50053; UBIQUITIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis;
KW Complete proteome; Cytoplasm; Disease mutation; Neurodegeneration;
KW Nucleus; Polymorphism; Reference proteome; Repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 624 Ubiquilin-2.
FT /FTId=PRO_0000211011.
FT DOMAIN 33 107 Ubiquitin-like.
FT REPEAT 491 493 1.
FT REPEAT 494 496 2.
FT REPEAT 497 499 3.
FT REPEAT 500 502 4.
FT REPEAT 503 505 5.
FT REPEAT 506 508 6.
FT REPEAT 509 511 7.
FT REPEAT 512 514 8.
FT REPEAT 515 517 9.
FT REPEAT 518 520 10.
FT REPEAT 521 523 11.
FT REPEAT 524 526 12.
FT DOMAIN 581 621 UBA.
FT REGION 491 526 12 X 3 AA tandem repeats of P-X-X.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 155 155 S -> N (in ALS15; uncertain pathological
FT significance).
FT /FTId=VAR_068892.
FT VARIANT 189 189 P -> T (in ALS15; uncertain pathological
FT significance).
FT /FTId=VAR_068893.
FT VARIANT 235 235 L -> H (in dbSNP:rs17002693).
FT /FTId=VAR_052680.
FT VARIANT 282 282 A -> V (probable disease-associated
FT mutation found in a patient with
FT frontotemporal dementia).
FT /FTId=VAR_068894.
FT VARIANT 283 283 A -> T (in ALS15).
FT /FTId=VAR_068895.
FT VARIANT 425 425 Q -> R (in ALS15).
FT /FTId=VAR_068896.
FT VARIANT 487 487 T -> I (in ALS15).
FT /FTId=VAR_068897.
FT VARIANT 497 497 P -> H (in ALS15; leads to defective
FT ubiquitin-mediated proteasomal
FT degradation).
FT /FTId=VAR_066562.
FT VARIANT 497 497 P -> S (in ALS15).
FT /FTId=VAR_066563.
FT VARIANT 506 506 P -> T (in ALS15; leads to defective
FT ubiquitin-mediated proteasomal
FT degradation).
FT /FTId=VAR_066564.
FT VARIANT 509 509 P -> S (in ALS15).
FT /FTId=VAR_066565.
FT VARIANT 525 525 P -> S (in ALS15).
FT /FTId=VAR_066566.
FT CONFLICT 544 544 S -> R (in Ref. 1 and 5).
FT STRAND 23 25
FT STRAND 33 38
FT STRAND 43 48
FT HELIX 54 65
FT STRAND 69 76
FT STRAND 79 82
FT HELIX 87 91
FT STRAND 93 102
SQ SEQUENCE 624 AA; 65696 MW; DF7DF8C4D7B71AC3 CRC64;
MAENGESSGP PRPSRGPAAA QGSAAAPAEP KIIKVTVKTP KEKEEFAVPE NSSVQQFKEA
ISKRFKSQTD QLVLIFAGKI LKDQDTLIQH GIHDGLTVHL VIKSQNRPQG QSTQPSNAAG
TNTTSASTPR SNSTPISTNS NPFGLGSLGG LAGLSSLGLS STNFSELQSQ MQQQLMASPE
MMIQIMENPF VQSMLSNPDL MRQLIMANPQ MQQLIQRNPE ISHLLNNPDI MRQTLEIARN
PAMMQEMMRN QDLALSNLES IPGGYNALRR MYTDIQEPML NAAQEQFGGN PFASVGSSSS
SGEGTQPSRT ENRDPLPNPW APPPATQSSA TTSTTTSTGS GSGNSSSNAT GNTVAAANYV
ASIFSTPGMQ SLLQQITENP QLIQNMLSAP YMRSMMQSLS QNPDLAAQMM LNSPLFTANP
QLQEQMRPQL PAFLQQMQNP DTLSAMSNPR AMQALMQIQQ GLQTLATEAP GLIPSFTPGV
GVGVLGTAIG PVGPVTPIGP IGPIVPFTPI GPIGPIGPTG PAAPPGSTGS GGPTGPTVSS
AAPSETTSPT SESGPNQQFI QQMVQALAGA NAPQLPNPEV RFQQQLEQLN AMGFLNREAN
LQALIATGGD INAAIERLLG SQPS
//
MIM
300264
*RECORD*
*FIELD* NO
300264
*FIELD* TI
*300264 UBIQUILIN 2; UBQLN2
;;PLIC2, MOUSE, HOMOLOG OF; PLIC2;;
CHAP1
*FIELD* TX
CLONING
read more
By performing independent yeast 2-hybrid screens, Kleijnen et al. (2000)
isolated cDNAs encoding PLIC1 (UBQLN1; 605046) and PLIC2, homologs of
the mouse Plics (proteins linking integrin-associated protein (IAP;
601028) and cytoskeleton) and the yeast Dsk2 protein. The predicted
624-amino acid PLIC2 protein, also called UBQLN2, shares 72% amino acid
identity with PLIC1. Two motifs are conserved in the mammalian PLICs and
yeast Dsk2, an N-terminal ubiquitin (191339)-like (UBL) domain and a
C-terminal ubiquitin-associated (UBA) domain. Unlike ubiquitin, the UBL
domain of the PLICs does not have a diglycine motif in its C terminus;
the diglycine motif serves as a target site for cellular hydrolases that
release ubiquitin from precursor fusion proteins. The absence of a GG
sequence suggests that the UBL domain in the PLICs is an integral part
of the open reading frame. The UBA domain is a loosely defined sequence
motif present in multiple enzyme classes of the ubiquitination
machinery. The most notable difference between the mammalian PLICs is
the presence of a collagen-like motif in PLIC2 that is absent in PLIC1
and yeast Dsk2. This domain is most homologous to the collagen-like
oncoprotein of Herpesvirus saimiri, STP-C488, which is implicated in
intracellular signaling via the RAS-RAF pathway (see 190020). The
collagen-like domain of PLIC2 contains 8 PXGP motifs that are
susceptible to cleavage by collagenase in vitro. Kleijnen et al. (2000)
showed that the human PLICs physically associate with both proteasomes
and ubiquitin ligases in large complexes. Overexpression of PLICs
interfered with the in vivo degradation of 2 unrelated
ubiquitin-dependent proteasome substrates, p53 (191170) and
I-kappa-B-alpha (NFKBIA; 164008), but not a ubiquitin-independent
substrate. These findings raised the possibility that the PLICs, and
possibly related ubiquitin-like family members, may functionally link
the ubiquitination machinery to the proteasome to affect in vivo protein
degradation.
By screening a human lung 2-hybrid cDNA library using a pGBT9-STCH
(601100) plasmid as bait, Kaye et al. (2000) isolated a cDNA encoding
UBQLN2, which they termed CHAP1/DSK2. Mutation analysis determined that
the C-terminal Sti1-like repeat sequence, but neither the N-terminal UBL
domain nor the C-terminal UBA domain, is required for binding of UBQLN2
to the ATPase domain of STCH.
GENE FUNCTION
Ubiquilin-2 is a member of the ubiquitin-like protein family. Humans
have 4 ubiquilin genes, each encoding a separate protein. Ubiquilins are
characterized by the presence of an N-terminal ubiquitin-like domain and
a C-terminal ubiquitin-associated domain. The middle part of ubiquilins
is highly variable. The ubiquitin-like domain of the ubiquilins bind to
subunits in the proteasome and the ubiquitin-associated domain binds to
the polyubiquitin chains that are typically conjugated onto proteins
marked for degradation by the proteasome. Ubiquilin-2 has a unique
repeat region containing 12 PXX tandem repeats (summary by Deng et al.,
2011).
GENE STRUCTURE
The UBQLN2 gene is intronless (Deng et al., 2011).
MAPPING
By radiation hybrid analysis, Kaye and Shows (2000) mapped the UBQLN2
gene to chromosome Xp11.23-p11.1, a location linked to a number of
neuropsychiatric disorders.
MOLECULAR GENETICS
Deng et al. (2011) identified 5 different mutations in ubiquilin-2 as
causative of a familial form of ALS that is X-linked but 90% penetrant
in females (ALS15; 300857). Each mutation involved proline residues in
the PXX repeat region that is unique to UBQLN2. Functional analysis
showed that these proline substitutions led to an impairment of protein
degradation.
*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO497HIS
In a 5-generation pedigree segregating apparently autosomal dominant ALS
but without any male-to-male transmission (ALS15; 300857), Deng et al.
(2011) identified a C-to-A transversion at nucleotide 1490 of the UBQLN2
gene, resulting in a pro-to-his substitution at codon 497 (P497H) of
ubiquilin-2. This mutation segregated with the disorder in all affected
family members. Two females were obligate carriers; 1 had not manifested
at the time of her death at age 72, and the other was asymptomatic at
age 71. One member of this family manifested ALS with dementia. This
mutation was not present in 928 ethnically matched control samples
representing 1,332 X chromosomes.
.0002
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO497SER
In a 3-generation family with apparently autosomal dominant ALS but
without male-to-male transmission (ALS15; 300857), Deng et al. (2011)
identified a C-to-T transition at nucleotide 1489 of the UBQLN2 gene,
resulting in a pro-to-ser substitution at codon 497 (P497S) of
ubiquilin-2. This mutation was not identified in 928 control samples.
Half of the patients in this family had ALS with dementia.
.0003
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO506THR
In a 3-generation pedigree segregating apparently autosomal dominant ALS
but with no male-to-male transmission (ALS15; 300857), Deng et al.
(2011) identified a C-to-A transversion at nucleotide 1516 of the UBQLN2
gene, resulting in a pro-to-thr substitution at codon 506 (P506T) of
ubiquilin-2. In this family there were individuals with isolated ALS as
well as ALS with dementia. There was also 1 obligate carrier, aged 50
and asymptomatic. This mutation was not identified in 928 ethnically
matched control samples.
.0004
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO509SER
In a family in which 2 sisters had ALS (ALS15; 300857), Deng et al.
(2011) found that both had a C-to-T transition at nucleotide 1525 of the
UBQLN2 gene, resulting in a pro-to-ser substitution at codon 509 (P509S)
of ubiquilin-2. This mutation was not observed in 928 ethnically matched
control samples.
.0005
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO525SER
Deng et al. (2011) identified 2 cousins with ALS (ALS15; 300857) who
shared a C-to-T transition at nucleotide 1573 of the UBQLN2 gene,
resulting in a pro-to-ser substitution at codon 525 (P525S) of
ubiquilin-2. This mutation was not observed in 928 ethnically matched
control samples. The cousins, male and female, had isolated ALS. The
mothers of the cousins were sisters and obligate carriers; 1 died at 94
years of age asymptomatic, and the other other died at 78 years
asymptomatic.
*FIELD* RF
1. Deng, H.-X.; Chen, W.; Hong, S.-T.; Boycott, K. M.; Gorrie, G.
H.; Siddique, N.; Yang, Y.; Fecto, F.; Shi, Y.; Zhai, H.; Jiang, H.;
Hirano, M.; and 11 others: Mutations in UBQLN2 cause dominant X-linked
juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215,
2011.
2. Kaye, F. J.; Modi, S.; Ivanovska, I.; Koonin, E. V.; Thress, K.;
Kubo, A.; Kornbluth, S.; Rose, M. D.: A family of ubiquitin-like
proteins binds the ATPase domain of Hsp70-like Stch. FEBS Lett. 467:
348-352, 2000.
3. Kaye, F. J.; Shows, T. B.: Assignment of ubiquilin 2 (UBQLN2)
to human chromosome xp11.23-p11.1 by GeneBridge radiation hybrids. Cytogenet.
Cell Genet. 89: 116-117, 2000.
4. Kleijnen, M. F.; Shih, A. H.; Zhou, P.; Kumar, S.; Soccio, R. E.;
Kedersha, N. L.; Gill, G.; Howley, P. M.: The hPLIC proteins may
provide a link between the ubiquitination machinery and the proteasome. Molec.
Cell 6: 409-419, 2000.
*FIELD* CN
Ada Hamosh - updated: 9/21/2011
Paul J. Converse - updated: 9/26/2000
*FIELD* CD
Stylianos E. Antonarakis: 9/14/2000
*FIELD* ED
alopez: 09/22/2011
terry: 9/21/2011
terry: 9/9/2010
wwang: 8/17/2010
carol: 5/12/2004
mgross: 9/26/2000
mgross: 9/14/2000
*RECORD*
*FIELD* NO
300264
*FIELD* TI
*300264 UBIQUILIN 2; UBQLN2
;;PLIC2, MOUSE, HOMOLOG OF; PLIC2;;
CHAP1
*FIELD* TX
CLONING
read more
By performing independent yeast 2-hybrid screens, Kleijnen et al. (2000)
isolated cDNAs encoding PLIC1 (UBQLN1; 605046) and PLIC2, homologs of
the mouse Plics (proteins linking integrin-associated protein (IAP;
601028) and cytoskeleton) and the yeast Dsk2 protein. The predicted
624-amino acid PLIC2 protein, also called UBQLN2, shares 72% amino acid
identity with PLIC1. Two motifs are conserved in the mammalian PLICs and
yeast Dsk2, an N-terminal ubiquitin (191339)-like (UBL) domain and a
C-terminal ubiquitin-associated (UBA) domain. Unlike ubiquitin, the UBL
domain of the PLICs does not have a diglycine motif in its C terminus;
the diglycine motif serves as a target site for cellular hydrolases that
release ubiquitin from precursor fusion proteins. The absence of a GG
sequence suggests that the UBL domain in the PLICs is an integral part
of the open reading frame. The UBA domain is a loosely defined sequence
motif present in multiple enzyme classes of the ubiquitination
machinery. The most notable difference between the mammalian PLICs is
the presence of a collagen-like motif in PLIC2 that is absent in PLIC1
and yeast Dsk2. This domain is most homologous to the collagen-like
oncoprotein of Herpesvirus saimiri, STP-C488, which is implicated in
intracellular signaling via the RAS-RAF pathway (see 190020). The
collagen-like domain of PLIC2 contains 8 PXGP motifs that are
susceptible to cleavage by collagenase in vitro. Kleijnen et al. (2000)
showed that the human PLICs physically associate with both proteasomes
and ubiquitin ligases in large complexes. Overexpression of PLICs
interfered with the in vivo degradation of 2 unrelated
ubiquitin-dependent proteasome substrates, p53 (191170) and
I-kappa-B-alpha (NFKBIA; 164008), but not a ubiquitin-independent
substrate. These findings raised the possibility that the PLICs, and
possibly related ubiquitin-like family members, may functionally link
the ubiquitination machinery to the proteasome to affect in vivo protein
degradation.
By screening a human lung 2-hybrid cDNA library using a pGBT9-STCH
(601100) plasmid as bait, Kaye et al. (2000) isolated a cDNA encoding
UBQLN2, which they termed CHAP1/DSK2. Mutation analysis determined that
the C-terminal Sti1-like repeat sequence, but neither the N-terminal UBL
domain nor the C-terminal UBA domain, is required for binding of UBQLN2
to the ATPase domain of STCH.
GENE FUNCTION
Ubiquilin-2 is a member of the ubiquitin-like protein family. Humans
have 4 ubiquilin genes, each encoding a separate protein. Ubiquilins are
characterized by the presence of an N-terminal ubiquitin-like domain and
a C-terminal ubiquitin-associated domain. The middle part of ubiquilins
is highly variable. The ubiquitin-like domain of the ubiquilins bind to
subunits in the proteasome and the ubiquitin-associated domain binds to
the polyubiquitin chains that are typically conjugated onto proteins
marked for degradation by the proteasome. Ubiquilin-2 has a unique
repeat region containing 12 PXX tandem repeats (summary by Deng et al.,
2011).
GENE STRUCTURE
The UBQLN2 gene is intronless (Deng et al., 2011).
MAPPING
By radiation hybrid analysis, Kaye and Shows (2000) mapped the UBQLN2
gene to chromosome Xp11.23-p11.1, a location linked to a number of
neuropsychiatric disorders.
MOLECULAR GENETICS
Deng et al. (2011) identified 5 different mutations in ubiquilin-2 as
causative of a familial form of ALS that is X-linked but 90% penetrant
in females (ALS15; 300857). Each mutation involved proline residues in
the PXX repeat region that is unique to UBQLN2. Functional analysis
showed that these proline substitutions led to an impairment of protein
degradation.
*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO497HIS
In a 5-generation pedigree segregating apparently autosomal dominant ALS
but without any male-to-male transmission (ALS15; 300857), Deng et al.
(2011) identified a C-to-A transversion at nucleotide 1490 of the UBQLN2
gene, resulting in a pro-to-his substitution at codon 497 (P497H) of
ubiquilin-2. This mutation segregated with the disorder in all affected
family members. Two females were obligate carriers; 1 had not manifested
at the time of her death at age 72, and the other was asymptomatic at
age 71. One member of this family manifested ALS with dementia. This
mutation was not present in 928 ethnically matched control samples
representing 1,332 X chromosomes.
.0002
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO497SER
In a 3-generation family with apparently autosomal dominant ALS but
without male-to-male transmission (ALS15; 300857), Deng et al. (2011)
identified a C-to-T transition at nucleotide 1489 of the UBQLN2 gene,
resulting in a pro-to-ser substitution at codon 497 (P497S) of
ubiquilin-2. This mutation was not identified in 928 control samples.
Half of the patients in this family had ALS with dementia.
.0003
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO506THR
In a 3-generation pedigree segregating apparently autosomal dominant ALS
but with no male-to-male transmission (ALS15; 300857), Deng et al.
(2011) identified a C-to-A transversion at nucleotide 1516 of the UBQLN2
gene, resulting in a pro-to-thr substitution at codon 506 (P506T) of
ubiquilin-2. In this family there were individuals with isolated ALS as
well as ALS with dementia. There was also 1 obligate carrier, aged 50
and asymptomatic. This mutation was not identified in 928 ethnically
matched control samples.
.0004
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO509SER
In a family in which 2 sisters had ALS (ALS15; 300857), Deng et al.
(2011) found that both had a C-to-T transition at nucleotide 1525 of the
UBQLN2 gene, resulting in a pro-to-ser substitution at codon 509 (P509S)
of ubiquilin-2. This mutation was not observed in 928 ethnically matched
control samples.
.0005
AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
UBQLN2, PRO525SER
Deng et al. (2011) identified 2 cousins with ALS (ALS15; 300857) who
shared a C-to-T transition at nucleotide 1573 of the UBQLN2 gene,
resulting in a pro-to-ser substitution at codon 525 (P525S) of
ubiquilin-2. This mutation was not observed in 928 ethnically matched
control samples. The cousins, male and female, had isolated ALS. The
mothers of the cousins were sisters and obligate carriers; 1 died at 94
years of age asymptomatic, and the other other died at 78 years
asymptomatic.
*FIELD* RF
1. Deng, H.-X.; Chen, W.; Hong, S.-T.; Boycott, K. M.; Gorrie, G.
H.; Siddique, N.; Yang, Y.; Fecto, F.; Shi, Y.; Zhai, H.; Jiang, H.;
Hirano, M.; and 11 others: Mutations in UBQLN2 cause dominant X-linked
juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215,
2011.
2. Kaye, F. J.; Modi, S.; Ivanovska, I.; Koonin, E. V.; Thress, K.;
Kubo, A.; Kornbluth, S.; Rose, M. D.: A family of ubiquitin-like
proteins binds the ATPase domain of Hsp70-like Stch. FEBS Lett. 467:
348-352, 2000.
3. Kaye, F. J.; Shows, T. B.: Assignment of ubiquilin 2 (UBQLN2)
to human chromosome xp11.23-p11.1 by GeneBridge radiation hybrids. Cytogenet.
Cell Genet. 89: 116-117, 2000.
4. Kleijnen, M. F.; Shih, A. H.; Zhou, P.; Kumar, S.; Soccio, R. E.;
Kedersha, N. L.; Gill, G.; Howley, P. M.: The hPLIC proteins may
provide a link between the ubiquitination machinery and the proteasome. Molec.
Cell 6: 409-419, 2000.
*FIELD* CN
Ada Hamosh - updated: 9/21/2011
Paul J. Converse - updated: 9/26/2000
*FIELD* CD
Stylianos E. Antonarakis: 9/14/2000
*FIELD* ED
alopez: 09/22/2011
terry: 9/21/2011
terry: 9/9/2010
wwang: 8/17/2010
carol: 5/12/2004
mgross: 9/26/2000
mgross: 9/14/2000
MIM
300857
*RECORD*
*FIELD* NO
300857
*FIELD* TI
#300857 AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA;
read moreALS15
*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
sclerosis-15 (ALS15) is caused by mutation in the UBQLN2 gene (300264).
For a general phenotypic description and a discussion of genetic
heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
CLINICAL FEATURES
Deng et al. (2011) identified a 5-generation family with ALS15 including
19 affected individuals. The disease was transmitted in a dominant
fashion with reduced penetrance in females. Deng et al. (2011) also
identified 4 other unrelated families with ALS15 and obtained clinical
data from a total of 40 individuals, including 35 patients and 5
obligate carriers. Penetrance was approximately 90% by age 70 years. The
age of onset of disease ranged from 16 to 71 years. There was a
significant difference in the age of onset between male and female
patients, with male patients having an earlier age of onset (33.9 +/-
14.0 years vs 47.3 +/- 10.8 years, P = 0.003, 2-tailed Student's
t-test). However, there were no statistically significant differences in
the duration of the disease (43.1 +/- 42.1 months vs 48.5 +/- 19.9
months, P = 0.61). Eight patients manifested both ALS and dementia.
Dementia in these patients was similar to frontotemporal lobar type (see
600274), including abnormalities in both behavior and executive
function. The dementia was progressive and eventually global in most
ALS/dementia patients. In some cases the dementia preceded motor
symptoms, but all patients eventually developed motor disability.
Pathologic analysis of spinal cord autopsy samples from 2 patients
revealed axonal loss in the corticospinal tract, loss of anterior horn
cells, and astrocytosis in the anterior horn of the spinal cord.
PATHOGENESIS
In ALS, protein aggregates or inclusions are most common in spinal motor
neurons and are typically skein-like in morphology. These
ubiquitin-positive inclusions, among others, are considered to be a
hallmark of ALS pathology. Deng et al. (2011) found that the skein-like
inclusions from 2 ALS15 patients were immunoreactive with both
ubiquilin-2 C-terminus and N-terminus antibodies, indicating that
ubiquilin-2 is involved in inclusion formation in X-linked ALS.
Furthermore, Deng et al. (2011) found that skein-like inclusions in the
X-linked patients were also immunoreactive with antibodies to
ALS-implicated proteins ubiquitin (see 191339), p62 (601530), TDP43
(605078), FUS (137070), and optineurin (602432), but not SOD1 (147450).
In the brains of patients with UBQLN2 mutations with ALS and dementia,
Deng et al. (2011) showed ubiquilin-2 inclusions in the hippocampus,
small inclusions in the neuropil, and large inclusions (up to 20 microns
in diameter) in some pyramidal neurons, especially those in the CA3 and
CA1 regions. Deng et al. (2011) noted that this type of hippocampal
pathology had not previously been observed in any other
neurodegenerative disorder. Among hippocampal sections from 15
pathologically characterized ALS cases without UBQLN2 mutations,
including 5 with dementia, Deng et al. (2011) observed prominent
ubiquilin-2 pathology in sections from the cases with dementia but not
in those from the 10 cases without dementia. The correlation of
hippocampal ubiquilin-2 pathology to dementia in ALS cases with or
without UBQLN2 mutations indicated that ubiquilin-2 is widely involved
in ALS-related dementia, even without UBQLN2 mutations.
MAPPING
Deng et al. (2011) performed linkage analysis with microsatellite
markers on the X chromosome in a 5-generation family with ALS and
obtained the highest 2-point lod score of 5.0 with marker DXS9736 at
theta = 0. Detailed mapping defined a 21.3-Mb minimum candidate region
containing 206 genes, of which 191 are protein-coding.
MOLECULAR GENETICS
Based on expression profile, function, structure, and potential
relevance of their encoded proteins, Deng et al. (2011) selected 41
genes for sequencing within the ALS15 candidate region. They identified
5 different proline substitutions in the PXX repeat domain of UBQLN2 as
causative of ALS15 in 5 unrelated families.
*FIELD* RF
1. Deng, H.-X.; Chen, W.; Hong, S.-T.; Boycott, K. M.; Gorrie, G.
H.; Siddique, N.; Yang, Y.; Fecto, F.; Shi, Y.; Zhai, H.; Jiang, H.;
Hirano, M.; and 11 others: Mutations in UBQLN2 cause dominant X-linked
juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215,
2011.
*FIELD* CD
Ada Hamosh: 9/21/2011
*FIELD* ED
alopez: 09/22/2011
*RECORD*
*FIELD* NO
300857
*FIELD* TI
#300857 AMYOTROPHIC LATERAL SCLEROSIS 15, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA;
read moreALS15
*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
sclerosis-15 (ALS15) is caused by mutation in the UBQLN2 gene (300264).
For a general phenotypic description and a discussion of genetic
heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
CLINICAL FEATURES
Deng et al. (2011) identified a 5-generation family with ALS15 including
19 affected individuals. The disease was transmitted in a dominant
fashion with reduced penetrance in females. Deng et al. (2011) also
identified 4 other unrelated families with ALS15 and obtained clinical
data from a total of 40 individuals, including 35 patients and 5
obligate carriers. Penetrance was approximately 90% by age 70 years. The
age of onset of disease ranged from 16 to 71 years. There was a
significant difference in the age of onset between male and female
patients, with male patients having an earlier age of onset (33.9 +/-
14.0 years vs 47.3 +/- 10.8 years, P = 0.003, 2-tailed Student's
t-test). However, there were no statistically significant differences in
the duration of the disease (43.1 +/- 42.1 months vs 48.5 +/- 19.9
months, P = 0.61). Eight patients manifested both ALS and dementia.
Dementia in these patients was similar to frontotemporal lobar type (see
600274), including abnormalities in both behavior and executive
function. The dementia was progressive and eventually global in most
ALS/dementia patients. In some cases the dementia preceded motor
symptoms, but all patients eventually developed motor disability.
Pathologic analysis of spinal cord autopsy samples from 2 patients
revealed axonal loss in the corticospinal tract, loss of anterior horn
cells, and astrocytosis in the anterior horn of the spinal cord.
PATHOGENESIS
In ALS, protein aggregates or inclusions are most common in spinal motor
neurons and are typically skein-like in morphology. These
ubiquitin-positive inclusions, among others, are considered to be a
hallmark of ALS pathology. Deng et al. (2011) found that the skein-like
inclusions from 2 ALS15 patients were immunoreactive with both
ubiquilin-2 C-terminus and N-terminus antibodies, indicating that
ubiquilin-2 is involved in inclusion formation in X-linked ALS.
Furthermore, Deng et al. (2011) found that skein-like inclusions in the
X-linked patients were also immunoreactive with antibodies to
ALS-implicated proteins ubiquitin (see 191339), p62 (601530), TDP43
(605078), FUS (137070), and optineurin (602432), but not SOD1 (147450).
In the brains of patients with UBQLN2 mutations with ALS and dementia,
Deng et al. (2011) showed ubiquilin-2 inclusions in the hippocampus,
small inclusions in the neuropil, and large inclusions (up to 20 microns
in diameter) in some pyramidal neurons, especially those in the CA3 and
CA1 regions. Deng et al. (2011) noted that this type of hippocampal
pathology had not previously been observed in any other
neurodegenerative disorder. Among hippocampal sections from 15
pathologically characterized ALS cases without UBQLN2 mutations,
including 5 with dementia, Deng et al. (2011) observed prominent
ubiquilin-2 pathology in sections from the cases with dementia but not
in those from the 10 cases without dementia. The correlation of
hippocampal ubiquilin-2 pathology to dementia in ALS cases with or
without UBQLN2 mutations indicated that ubiquilin-2 is widely involved
in ALS-related dementia, even without UBQLN2 mutations.
MAPPING
Deng et al. (2011) performed linkage analysis with microsatellite
markers on the X chromosome in a 5-generation family with ALS and
obtained the highest 2-point lod score of 5.0 with marker DXS9736 at
theta = 0. Detailed mapping defined a 21.3-Mb minimum candidate region
containing 206 genes, of which 191 are protein-coding.
MOLECULAR GENETICS
Based on expression profile, function, structure, and potential
relevance of their encoded proteins, Deng et al. (2011) selected 41
genes for sequencing within the ALS15 candidate region. They identified
5 different proline substitutions in the PXX repeat domain of UBQLN2 as
causative of ALS15 in 5 unrelated families.
*FIELD* RF
1. Deng, H.-X.; Chen, W.; Hong, S.-T.; Boycott, K. M.; Gorrie, G.
H.; Siddique, N.; Yang, Y.; Fecto, F.; Shi, Y.; Zhai, H.; Jiang, H.;
Hirano, M.; and 11 others: Mutations in UBQLN2 cause dominant X-linked
juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215,
2011.
*FIELD* CD
Ada Hamosh: 9/21/2011
*FIELD* ED
alopez: 09/22/2011