Full text data of CUL4B
CUL4B
(KIAA0695)
[Confidence: low (only semi-automatic identification from reviews)]
Cullin-4B; CUL-4B
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cullin-4B; CUL-4B
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q13620
ID CUL4B_HUMAN Reviewed; 913 AA.
AC Q13620; B1APK5; B3KVX4; B7Z5K8; Q6PIE4; Q6UP07; Q7Z673; Q9BY37;
read moreAC Q9UEB7; Q9UED7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 4.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Cullin-4B;
DE Short=CUL-4B;
GN Name=CUL4B; Synonyms=KIAA0695;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND INTERACTION WITH
RP CDT1.
RX PubMed=14578910; DOI=10.1038/ncb1061;
RA Higa L.A., Mihaylov I.S., Banks D.P., Zheng J., Zhang H.;
RT "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes
RT constitutes a new checkpoint.";
RL Nat. Cell Biol. 5:1008-1015(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Du M., Zu Z., Sansores-Garcia L., Wu K.K.;
RT "Molecular cloning of a full-length cullin, CUL4B and identification
RT of its interacting proteins.";
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Chondrocyte, Teratocarcinoma, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Fetal liver;
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 [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 133-913 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [9]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 626-913.
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [11]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [12]
RP INTERACTION WITH RBX1.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [13]
RP INTERACTION WITH TIP120A, AND IDENTIFICATION IN A COMPLEX WITH RBX1
RP AND TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [14]
RP FUNCTION, AND INTERACTION WITH CYCLIN E.
RX PubMed=16322693;
RA Higa L.A., Yang X., Zheng J., Banks D., Wu M., Ghosh P., Sun H.,
RA Zhang H.;
RT "Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors
RT Dacapo/p27Kip1 and cyclin E degradation.";
RL Cell Cycle 5:71-77(2006).
RN [15]
RP IDENTIFICATION IN COMPLEX WITH DDB1; DDB2 AND RBX1, MASS SPECTROMETRY,
RP AND FUNCTION.
RX PubMed=16678110; DOI=10.1016/j.molcel.2006.03.035;
RA Wang H., Zhai L., Xu J., Joo H.-Y., Jackson S., Erdjument-Bromage H.,
RA Tempst P., Xiong Y., Zhang Y.;
RT "Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin
RT ligase facilitates cellular response to DNA damage.";
RL Mol. Cell 22:383-394(2006).
RN [16]
RP INTERACTION WITH VPRBP; DDA1; DCAF6; DCAF17; DDB2 AND DCAF8.
RX PubMed=16949367; DOI=10.1016/j.molcel.2006.08.010;
RA Jin J., Arias E.E., Chen J., Harper J.W., Walter J.C.;
RT "A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2,
RT which is required for S phase destruction of the replication factor
RT Cdt1.";
RL Mol. Cell 23:709-721(2006).
RN [17]
RP INTERACTION WITH DTL; DDB2; TMEM113; WDR5B; WDR82; WDR26; GRWD1;
RP WDR51B; SNRNP40; DCAF8; WDR61; WDR76; WDR5; SMU1; TLE2 AND TLE3.
RX PubMed=17041588; DOI=10.1038/ncb1490;
RA Higa L.A., Wu M., Ye T., Kobayashi R., Sun H., Zhang H.;
RT "CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat
RT proteins and regulates histone methylation.";
RL Nat. Cell Biol. 8:1277-1283(2006).
RN [18]
RP INVOLVEMENT IN MRXS15.
RX PubMed=17273978; DOI=10.1086/512489;
RA Zou Y., Liu Q., Chen B., Zhang X., Guo C., Zhou H., Li J., Gao G.,
RA Guo Y., Yan C., Wei J., Shao C., Gong Y.;
RT "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin
RT ligase complex, causes X-linked mental retardation.";
RL Am. J. Hum. Genet. 80:561-566(2007).
RN [19]
RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=18593899; DOI=10.1158/0008-5472.CAN-07-6162;
RA Guerrero-Santoro J., Kapetanaki M.G., Hsieh C.L., Gorbachinsky I.,
RA Levine A.S., Rapic-Otrin V.;
RT "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to
RT UV-damaged chromatin and ubiquitinates histone H2A.";
RL Cancer Res. 68:5014-5022(2008).
RN [20]
RP FUNCTION, AND INTERACTION WITH MLST8.
RX PubMed=18235224;
RA Ghosh P., Wu M., Zhang H., Sun H.;
RT "mTORC1 signaling requires proteasomal function and the involvement of
RT CUL4-DDB1 ubiquitin E3 ligase.";
RL Cell Cycle 7:373-381(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-49; SER-53; SER-146 AND
RP SER-193, 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 [22]
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 [23]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KPNA2; KPNA4; KPNA1
RP AND KPNB1, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF LYS-55;
RP LYS-56; ARG-57; LYS-58 AND 55-LYS--LYS-58.
RX PubMed=19801544; DOI=10.1074/jbc.M109.050427;
RA Zou Y., Mi J., Cui J., Lu D., Zhang X., Guo C., Gao G., Liu Q.,
RA Chen B., Shao C., Gong Y.;
RT "Characterization of nuclear localization signal in the N terminus of
RT CUL4B and its essential role in cyclin E degradation and cell cycle
RT progression.";
RL J. Biol. Chem. 284:33320-33332(2009).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-49 AND SER-146, 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 [25]
RP DISEASE, AND INVOLVEMENT IN MRXS15.
RX PubMed=20002452; DOI=10.1111/j.1399-0004.2009.01331.x;
RA Badura-Stronka M., Jamsheer A., Materna-Kiryluk A., Sowinska A.,
RA Kiryluk K., Budny B., Latos-Bielenska A.;
RT "A novel nonsense mutation in CUL4B gene in three brothers with X-
RT linked mental retardation syndrome.";
RL Clin. Genet. 77:141-144(2010).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1 (ISOFORM 2),
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-8 AND SER-10 (ISOFORM
RP 2), AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [27]
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 [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [30]
RP STRUCTURE BY NMR OF 826-913.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the winged helix-turn-helix motif of human cul-
RT 4b.";
RL Submitted (APR-2007) to the PDB data bank.
RN [31]
RP VARIANTS MRXS15 ILE-213; CYS-572 AND ALA-745, AND VARIANT PRO-103.
RX PubMed=17236139; DOI=10.1086/511134;
RA Tarpey P.S., Raymond F.L., O'Meara S., Edkins S., Teague J.,
RA Butler A., Dicks E., Stevens C., Tofts C., Avis T., Barthorpe S.,
RA Buck G., Cole J., Gray K., Halliday K., Harrison R., Hills K.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Varian J., West S., Widaa S.,
RA Mallya U., Moon J., Luo Y., Holder S., Smithson S.F., Hurst J.A.,
RA Clayton-Smith J., Kerr B., Boyle J., Shaw M., Vandeleur L.,
RA Rodriguez J., Slaugh R., Easton D.F., Wooster R., Bobrow M.,
RA Srivastava A.K., Stevenson R.E., Schwartz C.E., Turner G., Gecz J.,
RA Futreal P.A., Stratton M.R., Partington M.;
RT "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit,
RT cause an X-linked mental retardation syndrome associated with
RT aggressive outbursts, seizures, relative macrocephaly, central
RT obesity, hypogonadism, pes cavus, and tremor.";
RL Am. J. Hum. Genet. 80:345-352(2007).
RN [32]
RP VARIANTS MRXS15 ILE-213; CYS-572 AND ALA-745.
RX PubMed=19377476; DOI=10.1038/ng.367;
RA Tarpey P.S., Smith R., Pleasance E., Whibley A., Edkins S., Hardy C.,
RA O'Meara S., Latimer C., Dicks E., Menzies A., Stephens P., Blow M.,
RA Greenman C., Xue Y., Tyler-Smith C., Thompson D., Gray K., Andrews J.,
RA Barthorpe S., Buck G., Cole J., Dunmore R., Jones D., Maddison M.,
RA Mironenko T., Turner R., Turrell K., Varian J., West S., Widaa S.,
RA Wray P., Teague J., Butler A., Jenkinson A., Jia M., Richardson D.,
RA Shepherd R., Wooster R., Tejada M.I., Martinez F., Carvill G.,
RA Goliath R., de Brouwer A.P., van Bokhoven H., Van Esch H., Chelly J.,
RA Raynaud M., Ropers H.H., Abidi F.E., Srivastava A.K., Cox J., Luo Y.,
RA Mallya U., Moon J., Parnau J., Mohammed S., Tolmie J.L.,
RA Shoubridge C., Corbett M., Gardner A., Haan E., Rujirabanjerd S.,
RA Shaw M., Vandeleur L., Fullston T., Easton D.F., Boyle J.,
RA Partington M., Hackett A., Field M., Skinner C., Stevenson R.E.,
RA Bobrow M., Turner G., Schwartz C.E., Gecz J., Raymond F.L.,
RA Futreal P.A., Stratton M.R.;
RT "A systematic, large-scale resequencing screen of X-chromosome coding
RT exons in mental retardation.";
RL Nat. Genet. 41:535-543(2009).
CC -!- FUNCTION: Core component of multiple cullin-RING-based E3
CC ubiquitin-protein ligase complexes which mediate the
CC ubiquitination and subsequent proteasomal degradation of target
CC proteins. The functional specificity of the E3 ubiquitin-protein
CC ligase complex depends on the variable substrate recognition
CC subunit. CUL4B may act within the complex as a scaffold protein,
CC contributing to catalysis through positioning of the substrate and
CC the ubiquitin-conjugating enzyme. Plays a role as part of the E3
CC ubiquitin-protein ligase complex in polyubiquitination of CDT1,
CC histone H2A, histone H3 and histone H4 in response to radiation-
CC induced DNA damage. Targeted to UV damaged chromatin by DDB2 and
CC may be important for DNA repair and DNA replication. Required for
CC ubiquitination of cyclin E, and consequently, normal G1 cell cycle
CC progression. Regulates the mammalian target-of-rapamycin (mTOR)
CC pathway involved in control of cell growth, size and metabolism.
CC Specific CUL4B regulation of the mTORC1-mediated pathway is
CC dependent upon 26S proteasome function and requires interaction
CC between CUL4B and MLST8.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-
CC protein ligase complexes that seem to be formed of DDB1, CUL4A or
CC CUL4B, RBX1 and a variable substrate recognition component which
CC seems to belong to a protein family described as DCAF (Ddb1- and
CC Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat)
CC proteins. Component of the DCX(DTL) complex with the putative
CC substrate recognition component DTL. Component of the DCX(DDB2)
CC complex with the putative substrate recognition component DDB2.
CC Part of a complex with RBX1 and TIP120A/CAND1. Interacts with RBX1
CC GRWD1, MLST8, SMU1, TLE2, TLE3, VPRBP, DDA1, DCAF6, DCAF17, DDB2,
CC DCAF8, TIP120A/CAND1 and TMEM113. Interacts with cyclin E and with
CC importins alpha-1 (KPNA2), alpha-3 (KPNA4), alpha-5 (KPNA1) and
CC beta-1 (KPNB1). May interact with WDR26, WDR51B, SNRNP40, WDR61,
CC WDR76 and WDR5.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=3; IntAct=EBI-456067, EBI-456077;
CC Q16531:DDB1; NbExp=15; IntAct=EBI-456067, EBI-350322;
CC P62877:RBX1; NbExp=4; IntAct=EBI-456067, EBI-398523;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q13620-2; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13620-1; Sequence=VSP_039085;
CC Note=Contains a N-acetylmethionine at position 1. Contains a
CC phosphoserine at position 8. Contains a phosphoserine at
CC position 10;
CC Name=3;
CC IsoId=Q13620-3; Sequence=VSP_039084, VSP_039086;
CC -!- PTM: Neddylated. Deneddylated via its interaction with the COP9
CC signalosome (CSN) complex.
CC -!- DISEASE: Mental retardation, X-linked, syndromic, 15 (MRXS15)
CC [MIM:300354]: A syndromic form of X-linked mental retardation
CC characterized by severe intellectual deficit associated with short
CC stature, craniofacial dysmorphism, small testes, muscle wasting in
CC lower legs, kyphosis, joint hyperextensibility, pes cavus, small
CC feet, and abnormalities of the toes. Additional neurologic
CC manifestations include speech delay and impairment, tremor,
CC seizures, gait ataxia, hyperactivity and decreased attention span.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the cullin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB67315.1; Type=Erroneous gene model prediction;
CC Sequence=AAK16812.1; Type=Frameshift; Positions=115;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CUL4B";
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DR EMBL; AY365125; AAR13073.1; -; mRNA.
DR EMBL; AF212995; AAK16812.1; ALT_FRAME; mRNA.
DR EMBL; AK123688; BAG53936.1; -; mRNA.
DR EMBL; AK299081; BAH12944.1; -; mRNA.
DR EMBL; AK315037; BAG37520.1; -; mRNA.
DR EMBL; BX537787; CAD97843.1; -; mRNA.
DR EMBL; AC002476; AAB67315.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL451005; CAI41370.1; -; Genomic_DNA.
DR EMBL; AC002476; CAI41370.1; JOINED; Genomic_DNA.
DR EMBL; CH471107; EAX11877.1; -; Genomic_DNA.
DR EMBL; BC036216; AAH36216.1; -; mRNA.
DR EMBL; AB014595; BAA31670.2; -; mRNA.
DR EMBL; U58091; AAC50548.1; -; mRNA.
DR RefSeq; NP_001073341.1; NM_001079872.1.
DR RefSeq; NP_003579.3; NM_003588.3.
DR RefSeq; XP_005262540.1; XM_005262483.1.
DR UniGene; Hs.102914; -.
DR PDB; 2DO7; NMR; -; A=826-913.
DR PDB; 4A0C; X-ray; 3.80 A; C/E=192-913.
DR PDB; 4A0L; X-ray; 7.40 A; E/H=192-913.
DR PDB; 4A64; X-ray; 2.57 A; A/B/C/D=206-557.
DR PDBsum; 2DO7; -.
DR PDBsum; 4A0C; -.
DR PDBsum; 4A0L; -.
DR PDBsum; 4A64; -.
DR ProteinModelPortal; Q13620; -.
DR SMR; Q13620; 206-913.
DR DIP; DIP-31609N; -.
DR IntAct; Q13620; 34.
DR MINT; MINT-4774381; -.
DR STRING; 9606.ENSP00000384109; -.
DR PhosphoSite; Q13620; -.
DR DMDM; 296439468; -.
DR PaxDb; Q13620; -.
DR PRIDE; Q13620; -.
DR DNASU; 8450; -.
DR Ensembl; ENST00000371322; ENSP00000360373; ENSG00000158290.
DR Ensembl; ENST00000404115; ENSP00000384109; ENSG00000158290.
DR GeneID; 8450; -.
DR KEGG; hsa:8450; -.
DR UCSC; uc004esw.3; human.
DR CTD; 8450; -.
DR GeneCards; GC0XM119658; -.
DR H-InvDB; HIX0017025; -.
DR HGNC; HGNC:2555; CUL4B.
DR HPA; CAB017786; -.
DR HPA; HPA011880; -.
DR MIM; 300304; gene.
DR MIM; 300354; phenotype.
DR neXtProt; NX_Q13620; -.
DR Orphanet; 85293; Cabezas syndrome.
DR PharmGKB; PA27051; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG003619; -.
DR KO; K10609; -.
DR OMA; KLRFEDS; -.
DR OrthoDB; EOG75TMB5; -.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q13620; -.
DR GeneWiki; CUL4B; -.
DR GenomeRNAi; 8450; -.
DR NextBio; 31618; -.
DR PMAP-CutDB; Q13620; -.
DR PRO; PR:Q13620; -.
DR ArrayExpress; Q13620; -.
DR Bgee; Q13620; -.
DR CleanEx; HS_CUL4B; -.
DR Genevestigator; Q13620; -.
DR GO; GO:0031465; C:Cul4B-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0007049; P:cell cycle; NAS:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell cycle;
KW Complete proteome; Disease mutation; DNA damage; DNA repair;
KW Isopeptide bond; Mental retardation; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 913 Cullin-4B.
FT /FTId=PRO_0000393946.
FT MOTIF 55 58 Nuclear localization signal.
FT COMPBIAS 3 193 Ser-rich.
FT MOD_RES 49 49 Phosphothreonine.
FT MOD_RES 53 53 Phosphoserine.
FT MOD_RES 146 146 Phosphoserine.
FT MOD_RES 193 193 Phosphoserine.
FT CROSSLNK 859 859 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8) (By
FT similarity).
FT VAR_SEQ 1 196 Missing (in isoform 3).
FT /FTId=VSP_039084.
FT VAR_SEQ 1 22 MMSQSSGSGDGNDDEATTSKDG -> MFPT (in
FT isoform 2).
FT /FTId=VSP_039085.
FT VAR_SEQ 197 203 LVIKNFK -> MIDPDFA (in isoform 3).
FT /FTId=VSP_039086.
FT VARIANT 103 103 L -> P (in dbSNP:rs61759504).
FT /FTId=VAR_032272.
FT VARIANT 213 213 T -> I (in MRXS15; uncertain pathological
FT significance).
FT /FTId=VAR_032273.
FT VARIANT 572 572 R -> C (in MRXS15).
FT /FTId=VAR_032274.
FT VARIANT 745 745 V -> A (in MRXS15).
FT /FTId=VAR_032275.
FT MUTAGEN 55 58 Missing: Distributed in cytoplasm. Fails
FT to promote cell proliferation. No binding
FT to KPNA2, KPNA4 and KPNA1.
FT MUTAGEN 55 55 K->A: No impairment in nuclear
FT localization.
FT MUTAGEN 56 56 K->A: Disrupts nuclear localization and
FT does not bind KPNA2, KPNA4, KPNA1; when
FT associated with A-57. Disrupts nuclear
FT localization.
FT MUTAGEN 57 57 R->A: Disrupts nuclear localization and
FT does not bind KPNA2, KPNA4, KPNA1; when
FT associated with A-56. Disrupts nuclear
FT localization.
FT MUTAGEN 58 58 K->A: No impairment in nuclear
FT localization.
FT CONFLICT 69 69 S -> R (in Ref. 3; BAG53936).
FT CONFLICT 126 126 E -> G (in Ref. 4; CAD97843).
FT CONFLICT 142 142 S -> P (in Ref. 3; BAG53936).
FT CONFLICT 196 196 K -> N (in Ref. 2; AAK16812).
FT CONFLICT 265 265 E -> G (in Ref. 3; BAG53936).
FT CONFLICT 268 268 I -> M (in Ref. 2; AAK16812).
FT CONFLICT 485 485 G -> D (in Ref. 4; CAD97843).
FT CONFLICT 664 664 Q -> QVK (in Ref. 2; AAK16812).
FT CONFLICT 727 727 L -> I (in Ref. 1; AAR13073 and 7;
FT AAH36216).
FT STRAND 210 212
FT HELIX 215 228
FT HELIX 237 250
FT HELIX 253 270
FT HELIX 271 276
FT HELIX 282 306
FT HELIX 308 312
FT TURN 315 317
FT HELIX 324 335
FT TURN 336 338
FT HELIX 340 358
FT HELIX 365 377
FT HELIX 381 384
FT HELIX 386 407
FT HELIX 410 430
FT HELIX 434 436
FT HELIX 437 448
FT HELIX 450 452
FT HELIX 453 466
FT HELIX 470 480
FT HELIX 486 507
FT STRAND 511 513
FT HELIX 515 533
FT HELIX 538 549
FT HELIX 841 860
FT STRAND 861 865
FT HELIX 866 876
FT HELIX 883 895
FT STRAND 898 901
FT STRAND 908 911
SQ SEQUENCE 913 AA; 103982 MW; 3E58C5868FDF0700 CRC64;
MMSQSSGSGD GNDDEATTSK DGGFSSPSPS AAAAAQEVRS ATDGNTSTTP PTSAKKRKLN
SSSSSSSNSS NEREDFDSTS SSSSTPPLQP RDSASPSTSS FCLGVSVAAS SHVPIQKKLR
FEDTLEFVGF DAKMAEESSS SSSSSSPTAA TSQQQQLKNK SILISSVASV HHANGLAKSS
TTVSSFANSK PGSAKKLVIK NFKDKPKLPE NYTDETWQKL KEAVEAIQNS TSIKYNLEEL
YQAVENLCSY KISANLYKQL RQICEDHIKA QIHQFREDSL DSVLFLKKID RCWQNHCRQM
IMIRSIFLFL DRTYVLQNSM LPSIWDMGLE LFRAHIISDQ KVQNKTIDGI LLLIERERNG
EAIDRSLLRS LLSMLSDLQI YQDSFEQRFL EETNRLYAAE GQKLMQEREV PEYLHHVNKR
LEEEADRLIT YLDQTTQKSL IATVEKQLLG EHLTAILQKG LNNLLDENRI QDLSLLYQLF
SRVRGGVQVL LQQWIEYIKA FGSTIVINPE KDKTMVQELL DFKDKVDHII DICFLKNEKF
INAMKEAFET FINKRPNKPA ELIAKYVDSK LRAGNKEATD EELEKMLDKI MIIFRFIYGK
DVFEAFYKKD LAKRLLVGKS ASVDAEKSML SKLKHECGAA FTSKLEGMFK DMELSKDIMI
QFKQYMQNQN VPGNIELTVN ILTMGYWPTY VPMEVHLPPE MVKLQEIFKT FYLGKHSGRK
LQWQSTLGHC VLKAEFKEGK KELQVSLFQT LVLLMFNEGE EFSLEEIKQA TGIEDGELRR
TLQSLACGKA RVLAKNPKGK DIEDGDKFIC NDDFKHKLFR IKINQIQMKE TVEEQASTTE
RVFQDRQYQI DAAIVRIMKM RKTLSHNLLV SEVYNQLKFP VKPADLKKRI ESLIDRDYME
RDKENPNQYN YIA
//
ID CUL4B_HUMAN Reviewed; 913 AA.
AC Q13620; B1APK5; B3KVX4; B7Z5K8; Q6PIE4; Q6UP07; Q7Z673; Q9BY37;
read moreAC Q9UEB7; Q9UED7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 4.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Cullin-4B;
DE Short=CUL-4B;
GN Name=CUL4B; Synonyms=KIAA0695;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND INTERACTION WITH
RP CDT1.
RX PubMed=14578910; DOI=10.1038/ncb1061;
RA Higa L.A., Mihaylov I.S., Banks D.P., Zheng J., Zhang H.;
RT "Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes
RT constitutes a new checkpoint.";
RL Nat. Cell Biol. 5:1008-1015(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Du M., Zu Z., Sansores-Garcia L., Wu K.K.;
RT "Molecular cloning of a full-length cullin, CUL4B and identification
RT of its interacting proteins.";
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Chondrocyte, Teratocarcinoma, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Fetal liver;
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 [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 133-913 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [9]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 626-913.
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [11]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [12]
RP INTERACTION WITH RBX1.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [13]
RP INTERACTION WITH TIP120A, AND IDENTIFICATION IN A COMPLEX WITH RBX1
RP AND TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [14]
RP FUNCTION, AND INTERACTION WITH CYCLIN E.
RX PubMed=16322693;
RA Higa L.A., Yang X., Zheng J., Banks D., Wu M., Ghosh P., Sun H.,
RA Zhang H.;
RT "Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors
RT Dacapo/p27Kip1 and cyclin E degradation.";
RL Cell Cycle 5:71-77(2006).
RN [15]
RP IDENTIFICATION IN COMPLEX WITH DDB1; DDB2 AND RBX1, MASS SPECTROMETRY,
RP AND FUNCTION.
RX PubMed=16678110; DOI=10.1016/j.molcel.2006.03.035;
RA Wang H., Zhai L., Xu J., Joo H.-Y., Jackson S., Erdjument-Bromage H.,
RA Tempst P., Xiong Y., Zhang Y.;
RT "Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin
RT ligase facilitates cellular response to DNA damage.";
RL Mol. Cell 22:383-394(2006).
RN [16]
RP INTERACTION WITH VPRBP; DDA1; DCAF6; DCAF17; DDB2 AND DCAF8.
RX PubMed=16949367; DOI=10.1016/j.molcel.2006.08.010;
RA Jin J., Arias E.E., Chen J., Harper J.W., Walter J.C.;
RT "A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2,
RT which is required for S phase destruction of the replication factor
RT Cdt1.";
RL Mol. Cell 23:709-721(2006).
RN [17]
RP INTERACTION WITH DTL; DDB2; TMEM113; WDR5B; WDR82; WDR26; GRWD1;
RP WDR51B; SNRNP40; DCAF8; WDR61; WDR76; WDR5; SMU1; TLE2 AND TLE3.
RX PubMed=17041588; DOI=10.1038/ncb1490;
RA Higa L.A., Wu M., Ye T., Kobayashi R., Sun H., Zhang H.;
RT "CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat
RT proteins and regulates histone methylation.";
RL Nat. Cell Biol. 8:1277-1283(2006).
RN [18]
RP INVOLVEMENT IN MRXS15.
RX PubMed=17273978; DOI=10.1086/512489;
RA Zou Y., Liu Q., Chen B., Zhang X., Guo C., Zhou H., Li J., Gao G.,
RA Guo Y., Yan C., Wei J., Shao C., Gong Y.;
RT "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin
RT ligase complex, causes X-linked mental retardation.";
RL Am. J. Hum. Genet. 80:561-566(2007).
RN [19]
RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=18593899; DOI=10.1158/0008-5472.CAN-07-6162;
RA Guerrero-Santoro J., Kapetanaki M.G., Hsieh C.L., Gorbachinsky I.,
RA Levine A.S., Rapic-Otrin V.;
RT "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to
RT UV-damaged chromatin and ubiquitinates histone H2A.";
RL Cancer Res. 68:5014-5022(2008).
RN [20]
RP FUNCTION, AND INTERACTION WITH MLST8.
RX PubMed=18235224;
RA Ghosh P., Wu M., Zhang H., Sun H.;
RT "mTORC1 signaling requires proteasomal function and the involvement of
RT CUL4-DDB1 ubiquitin E3 ligase.";
RL Cell Cycle 7:373-381(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-49; SER-53; SER-146 AND
RP SER-193, 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 [22]
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 [23]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH KPNA2; KPNA4; KPNA1
RP AND KPNB1, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF LYS-55;
RP LYS-56; ARG-57; LYS-58 AND 55-LYS--LYS-58.
RX PubMed=19801544; DOI=10.1074/jbc.M109.050427;
RA Zou Y., Mi J., Cui J., Lu D., Zhang X., Guo C., Gao G., Liu Q.,
RA Chen B., Shao C., Gong Y.;
RT "Characterization of nuclear localization signal in the N terminus of
RT CUL4B and its essential role in cyclin E degradation and cell cycle
RT progression.";
RL J. Biol. Chem. 284:33320-33332(2009).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-49 AND SER-146, 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 [25]
RP DISEASE, AND INVOLVEMENT IN MRXS15.
RX PubMed=20002452; DOI=10.1111/j.1399-0004.2009.01331.x;
RA Badura-Stronka M., Jamsheer A., Materna-Kiryluk A., Sowinska A.,
RA Kiryluk K., Budny B., Latos-Bielenska A.;
RT "A novel nonsense mutation in CUL4B gene in three brothers with X-
RT linked mental retardation syndrome.";
RL Clin. Genet. 77:141-144(2010).
RN [26]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1 (ISOFORM 2),
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-8 AND SER-10 (ISOFORM
RP 2), AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [27]
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 [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [30]
RP STRUCTURE BY NMR OF 826-913.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the winged helix-turn-helix motif of human cul-
RT 4b.";
RL Submitted (APR-2007) to the PDB data bank.
RN [31]
RP VARIANTS MRXS15 ILE-213; CYS-572 AND ALA-745, AND VARIANT PRO-103.
RX PubMed=17236139; DOI=10.1086/511134;
RA Tarpey P.S., Raymond F.L., O'Meara S., Edkins S., Teague J.,
RA Butler A., Dicks E., Stevens C., Tofts C., Avis T., Barthorpe S.,
RA Buck G., Cole J., Gray K., Halliday K., Harrison R., Hills K.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Varian J., West S., Widaa S.,
RA Mallya U., Moon J., Luo Y., Holder S., Smithson S.F., Hurst J.A.,
RA Clayton-Smith J., Kerr B., Boyle J., Shaw M., Vandeleur L.,
RA Rodriguez J., Slaugh R., Easton D.F., Wooster R., Bobrow M.,
RA Srivastava A.K., Stevenson R.E., Schwartz C.E., Turner G., Gecz J.,
RA Futreal P.A., Stratton M.R., Partington M.;
RT "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit,
RT cause an X-linked mental retardation syndrome associated with
RT aggressive outbursts, seizures, relative macrocephaly, central
RT obesity, hypogonadism, pes cavus, and tremor.";
RL Am. J. Hum. Genet. 80:345-352(2007).
RN [32]
RP VARIANTS MRXS15 ILE-213; CYS-572 AND ALA-745.
RX PubMed=19377476; DOI=10.1038/ng.367;
RA Tarpey P.S., Smith R., Pleasance E., Whibley A., Edkins S., Hardy C.,
RA O'Meara S., Latimer C., Dicks E., Menzies A., Stephens P., Blow M.,
RA Greenman C., Xue Y., Tyler-Smith C., Thompson D., Gray K., Andrews J.,
RA Barthorpe S., Buck G., Cole J., Dunmore R., Jones D., Maddison M.,
RA Mironenko T., Turner R., Turrell K., Varian J., West S., Widaa S.,
RA Wray P., Teague J., Butler A., Jenkinson A., Jia M., Richardson D.,
RA Shepherd R., Wooster R., Tejada M.I., Martinez F., Carvill G.,
RA Goliath R., de Brouwer A.P., van Bokhoven H., Van Esch H., Chelly J.,
RA Raynaud M., Ropers H.H., Abidi F.E., Srivastava A.K., Cox J., Luo Y.,
RA Mallya U., Moon J., Parnau J., Mohammed S., Tolmie J.L.,
RA Shoubridge C., Corbett M., Gardner A., Haan E., Rujirabanjerd S.,
RA Shaw M., Vandeleur L., Fullston T., Easton D.F., Boyle J.,
RA Partington M., Hackett A., Field M., Skinner C., Stevenson R.E.,
RA Bobrow M., Turner G., Schwartz C.E., Gecz J., Raymond F.L.,
RA Futreal P.A., Stratton M.R.;
RT "A systematic, large-scale resequencing screen of X-chromosome coding
RT exons in mental retardation.";
RL Nat. Genet. 41:535-543(2009).
CC -!- FUNCTION: Core component of multiple cullin-RING-based E3
CC ubiquitin-protein ligase complexes which mediate the
CC ubiquitination and subsequent proteasomal degradation of target
CC proteins. The functional specificity of the E3 ubiquitin-protein
CC ligase complex depends on the variable substrate recognition
CC subunit. CUL4B may act within the complex as a scaffold protein,
CC contributing to catalysis through positioning of the substrate and
CC the ubiquitin-conjugating enzyme. Plays a role as part of the E3
CC ubiquitin-protein ligase complex in polyubiquitination of CDT1,
CC histone H2A, histone H3 and histone H4 in response to radiation-
CC induced DNA damage. Targeted to UV damaged chromatin by DDB2 and
CC may be important for DNA repair and DNA replication. Required for
CC ubiquitination of cyclin E, and consequently, normal G1 cell cycle
CC progression. Regulates the mammalian target-of-rapamycin (mTOR)
CC pathway involved in control of cell growth, size and metabolism.
CC Specific CUL4B regulation of the mTORC1-mediated pathway is
CC dependent upon 26S proteasome function and requires interaction
CC between CUL4B and MLST8.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-
CC protein ligase complexes that seem to be formed of DDB1, CUL4A or
CC CUL4B, RBX1 and a variable substrate recognition component which
CC seems to belong to a protein family described as DCAF (Ddb1- and
CC Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat)
CC proteins. Component of the DCX(DTL) complex with the putative
CC substrate recognition component DTL. Component of the DCX(DDB2)
CC complex with the putative substrate recognition component DDB2.
CC Part of a complex with RBX1 and TIP120A/CAND1. Interacts with RBX1
CC GRWD1, MLST8, SMU1, TLE2, TLE3, VPRBP, DDA1, DCAF6, DCAF17, DDB2,
CC DCAF8, TIP120A/CAND1 and TMEM113. Interacts with cyclin E and with
CC importins alpha-1 (KPNA2), alpha-3 (KPNA4), alpha-5 (KPNA1) and
CC beta-1 (KPNB1). May interact with WDR26, WDR51B, SNRNP40, WDR61,
CC WDR76 and WDR5.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=3; IntAct=EBI-456067, EBI-456077;
CC Q16531:DDB1; NbExp=15; IntAct=EBI-456067, EBI-350322;
CC P62877:RBX1; NbExp=4; IntAct=EBI-456067, EBI-398523;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q13620-2; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13620-1; Sequence=VSP_039085;
CC Note=Contains a N-acetylmethionine at position 1. Contains a
CC phosphoserine at position 8. Contains a phosphoserine at
CC position 10;
CC Name=3;
CC IsoId=Q13620-3; Sequence=VSP_039084, VSP_039086;
CC -!- PTM: Neddylated. Deneddylated via its interaction with the COP9
CC signalosome (CSN) complex.
CC -!- DISEASE: Mental retardation, X-linked, syndromic, 15 (MRXS15)
CC [MIM:300354]: A syndromic form of X-linked mental retardation
CC characterized by severe intellectual deficit associated with short
CC stature, craniofacial dysmorphism, small testes, muscle wasting in
CC lower legs, kyphosis, joint hyperextensibility, pes cavus, small
CC feet, and abnormalities of the toes. Additional neurologic
CC manifestations include speech delay and impairment, tremor,
CC seizures, gait ataxia, hyperactivity and decreased attention span.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the cullin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB67315.1; Type=Erroneous gene model prediction;
CC Sequence=AAK16812.1; Type=Frameshift; Positions=115;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CUL4B";
CC -----------------------------------------------------------------------
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DR EMBL; AY365125; AAR13073.1; -; mRNA.
DR EMBL; AF212995; AAK16812.1; ALT_FRAME; mRNA.
DR EMBL; AK123688; BAG53936.1; -; mRNA.
DR EMBL; AK299081; BAH12944.1; -; mRNA.
DR EMBL; AK315037; BAG37520.1; -; mRNA.
DR EMBL; BX537787; CAD97843.1; -; mRNA.
DR EMBL; AC002476; AAB67315.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL451005; CAI41370.1; -; Genomic_DNA.
DR EMBL; AC002476; CAI41370.1; JOINED; Genomic_DNA.
DR EMBL; CH471107; EAX11877.1; -; Genomic_DNA.
DR EMBL; BC036216; AAH36216.1; -; mRNA.
DR EMBL; AB014595; BAA31670.2; -; mRNA.
DR EMBL; U58091; AAC50548.1; -; mRNA.
DR RefSeq; NP_001073341.1; NM_001079872.1.
DR RefSeq; NP_003579.3; NM_003588.3.
DR RefSeq; XP_005262540.1; XM_005262483.1.
DR UniGene; Hs.102914; -.
DR PDB; 2DO7; NMR; -; A=826-913.
DR PDB; 4A0C; X-ray; 3.80 A; C/E=192-913.
DR PDB; 4A0L; X-ray; 7.40 A; E/H=192-913.
DR PDB; 4A64; X-ray; 2.57 A; A/B/C/D=206-557.
DR PDBsum; 2DO7; -.
DR PDBsum; 4A0C; -.
DR PDBsum; 4A0L; -.
DR PDBsum; 4A64; -.
DR ProteinModelPortal; Q13620; -.
DR SMR; Q13620; 206-913.
DR DIP; DIP-31609N; -.
DR IntAct; Q13620; 34.
DR MINT; MINT-4774381; -.
DR STRING; 9606.ENSP00000384109; -.
DR PhosphoSite; Q13620; -.
DR DMDM; 296439468; -.
DR PaxDb; Q13620; -.
DR PRIDE; Q13620; -.
DR DNASU; 8450; -.
DR Ensembl; ENST00000371322; ENSP00000360373; ENSG00000158290.
DR Ensembl; ENST00000404115; ENSP00000384109; ENSG00000158290.
DR GeneID; 8450; -.
DR KEGG; hsa:8450; -.
DR UCSC; uc004esw.3; human.
DR CTD; 8450; -.
DR GeneCards; GC0XM119658; -.
DR H-InvDB; HIX0017025; -.
DR HGNC; HGNC:2555; CUL4B.
DR HPA; CAB017786; -.
DR HPA; HPA011880; -.
DR MIM; 300304; gene.
DR MIM; 300354; phenotype.
DR neXtProt; NX_Q13620; -.
DR Orphanet; 85293; Cabezas syndrome.
DR PharmGKB; PA27051; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG003619; -.
DR KO; K10609; -.
DR OMA; KLRFEDS; -.
DR OrthoDB; EOG75TMB5; -.
DR UniPathway; UPA00143; -.
DR EvolutionaryTrace; Q13620; -.
DR GeneWiki; CUL4B; -.
DR GenomeRNAi; 8450; -.
DR NextBio; 31618; -.
DR PMAP-CutDB; Q13620; -.
DR PRO; PR:Q13620; -.
DR ArrayExpress; Q13620; -.
DR Bgee; Q13620; -.
DR CleanEx; HS_CUL4B; -.
DR Genevestigator; Q13620; -.
DR GO; GO:0031465; C:Cul4B-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0007049; P:cell cycle; NAS:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell cycle;
KW Complete proteome; Disease mutation; DNA damage; DNA repair;
KW Isopeptide bond; Mental retardation; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 913 Cullin-4B.
FT /FTId=PRO_0000393946.
FT MOTIF 55 58 Nuclear localization signal.
FT COMPBIAS 3 193 Ser-rich.
FT MOD_RES 49 49 Phosphothreonine.
FT MOD_RES 53 53 Phosphoserine.
FT MOD_RES 146 146 Phosphoserine.
FT MOD_RES 193 193 Phosphoserine.
FT CROSSLNK 859 859 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8) (By
FT similarity).
FT VAR_SEQ 1 196 Missing (in isoform 3).
FT /FTId=VSP_039084.
FT VAR_SEQ 1 22 MMSQSSGSGDGNDDEATTSKDG -> MFPT (in
FT isoform 2).
FT /FTId=VSP_039085.
FT VAR_SEQ 197 203 LVIKNFK -> MIDPDFA (in isoform 3).
FT /FTId=VSP_039086.
FT VARIANT 103 103 L -> P (in dbSNP:rs61759504).
FT /FTId=VAR_032272.
FT VARIANT 213 213 T -> I (in MRXS15; uncertain pathological
FT significance).
FT /FTId=VAR_032273.
FT VARIANT 572 572 R -> C (in MRXS15).
FT /FTId=VAR_032274.
FT VARIANT 745 745 V -> A (in MRXS15).
FT /FTId=VAR_032275.
FT MUTAGEN 55 58 Missing: Distributed in cytoplasm. Fails
FT to promote cell proliferation. No binding
FT to KPNA2, KPNA4 and KPNA1.
FT MUTAGEN 55 55 K->A: No impairment in nuclear
FT localization.
FT MUTAGEN 56 56 K->A: Disrupts nuclear localization and
FT does not bind KPNA2, KPNA4, KPNA1; when
FT associated with A-57. Disrupts nuclear
FT localization.
FT MUTAGEN 57 57 R->A: Disrupts nuclear localization and
FT does not bind KPNA2, KPNA4, KPNA1; when
FT associated with A-56. Disrupts nuclear
FT localization.
FT MUTAGEN 58 58 K->A: No impairment in nuclear
FT localization.
FT CONFLICT 69 69 S -> R (in Ref. 3; BAG53936).
FT CONFLICT 126 126 E -> G (in Ref. 4; CAD97843).
FT CONFLICT 142 142 S -> P (in Ref. 3; BAG53936).
FT CONFLICT 196 196 K -> N (in Ref. 2; AAK16812).
FT CONFLICT 265 265 E -> G (in Ref. 3; BAG53936).
FT CONFLICT 268 268 I -> M (in Ref. 2; AAK16812).
FT CONFLICT 485 485 G -> D (in Ref. 4; CAD97843).
FT CONFLICT 664 664 Q -> QVK (in Ref. 2; AAK16812).
FT CONFLICT 727 727 L -> I (in Ref. 1; AAR13073 and 7;
FT AAH36216).
FT STRAND 210 212
FT HELIX 215 228
FT HELIX 237 250
FT HELIX 253 270
FT HELIX 271 276
FT HELIX 282 306
FT HELIX 308 312
FT TURN 315 317
FT HELIX 324 335
FT TURN 336 338
FT HELIX 340 358
FT HELIX 365 377
FT HELIX 381 384
FT HELIX 386 407
FT HELIX 410 430
FT HELIX 434 436
FT HELIX 437 448
FT HELIX 450 452
FT HELIX 453 466
FT HELIX 470 480
FT HELIX 486 507
FT STRAND 511 513
FT HELIX 515 533
FT HELIX 538 549
FT HELIX 841 860
FT STRAND 861 865
FT HELIX 866 876
FT HELIX 883 895
FT STRAND 898 901
FT STRAND 908 911
SQ SEQUENCE 913 AA; 103982 MW; 3E58C5868FDF0700 CRC64;
MMSQSSGSGD GNDDEATTSK DGGFSSPSPS AAAAAQEVRS ATDGNTSTTP PTSAKKRKLN
SSSSSSSNSS NEREDFDSTS SSSSTPPLQP RDSASPSTSS FCLGVSVAAS SHVPIQKKLR
FEDTLEFVGF DAKMAEESSS SSSSSSPTAA TSQQQQLKNK SILISSVASV HHANGLAKSS
TTVSSFANSK PGSAKKLVIK NFKDKPKLPE NYTDETWQKL KEAVEAIQNS TSIKYNLEEL
YQAVENLCSY KISANLYKQL RQICEDHIKA QIHQFREDSL DSVLFLKKID RCWQNHCRQM
IMIRSIFLFL DRTYVLQNSM LPSIWDMGLE LFRAHIISDQ KVQNKTIDGI LLLIERERNG
EAIDRSLLRS LLSMLSDLQI YQDSFEQRFL EETNRLYAAE GQKLMQEREV PEYLHHVNKR
LEEEADRLIT YLDQTTQKSL IATVEKQLLG EHLTAILQKG LNNLLDENRI QDLSLLYQLF
SRVRGGVQVL LQQWIEYIKA FGSTIVINPE KDKTMVQELL DFKDKVDHII DICFLKNEKF
INAMKEAFET FINKRPNKPA ELIAKYVDSK LRAGNKEATD EELEKMLDKI MIIFRFIYGK
DVFEAFYKKD LAKRLLVGKS ASVDAEKSML SKLKHECGAA FTSKLEGMFK DMELSKDIMI
QFKQYMQNQN VPGNIELTVN ILTMGYWPTY VPMEVHLPPE MVKLQEIFKT FYLGKHSGRK
LQWQSTLGHC VLKAEFKEGK KELQVSLFQT LVLLMFNEGE EFSLEEIKQA TGIEDGELRR
TLQSLACGKA RVLAKNPKGK DIEDGDKFIC NDDFKHKLFR IKINQIQMKE TVEEQASTTE
RVFQDRQYQI DAAIVRIMKM RKTLSHNLLV SEVYNQLKFP VKPADLKKRI ESLIDRDYME
RDKENPNQYN YIA
//
MIM
300304
*RECORD*
*FIELD* NO
300304
*FIELD* TI
*300304 CULLIN 4B; CUL4B
;;KIAA0695
*FIELD* TX
CLONING
Kipreos et al. (1996) identified the cullin gene family, which includes
read moreat least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae.
Human CUL4A (603137) and CUL4B are orthologs of nematode cul4. The
partial C-terminal amino acid sequences of CUL4A and CUL4B share 88%
identity. Rasooly (1998) found that a brain cDNA isolated by Ishikawa et
al. (1998), KIAA0695, was 99% identical to CUL4B. Using RT-PCR, Ishikawa
et al. (1998) determined that KIAA0695 is expressed ubiquitously.
Tarpey et al. (2007) reported that the CUL4B gene encodes a protein of
913 amino acids. The cullin domain is located between amino acid
residues 217 and 815 and is characterized a by C-terminal globular
domain (cullin homology domain) and a series of N-terminal repeats
(cullin repeats).
GENE STRUCTURE
The CUL4B gene contains 22 exons (Tarpey et al., 2007).
MAPPING
Although Ishikawa et al. (1998) mapped the KIAA0695 gene to human
chromosome 10, Rasooly (1998) noted the presence of sequences in GenBank
(GENBANK AC002476) identical to CUL4B within a cloned region in Xq23.
Tarpey et al. (2007) placed the CUL4B gene in Xq24.
GENE FUNCTION
Zhong et al. (2003) showed that the CUL4 ubiquitin ligase temporally
restricts DNA replication licensing in Caenorhabditis elegans.
Inactivation of CUL4 causes massive DNA rereplication, producing cells
with up to 100C DNA content. The C. elegans ortholog of the
replication-licensing factor CDT1 (605525) is required for DNA
replication. C. elegans CDT1 is present in G1-phase nuclei but
disappears as cells enter S phase. In cells lacking CUL4, CDT1 levels
failed to decrease during S phase and instead remained constant in the
rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the
CUL4 rereplication phenotype. Zhong et al. (2003) proposed that CUL4
prevents aberrant reinitiation of DNA replication, at least in part, by
facilitating the degradation of CDT1.
By mass spectrometric analysis, Higa et al. (2006) identified over 20
WD40 repeat-containing (WDR) proteins that interacted with the CUL4-DDB1
(600045)-ROC1 (RBX1; 603814) complex. Sequence alignment revealed that
most of the interacting WDR proteins had a centrally positioned WDxR/K
submotif. Knockdown studies suggested that the WDR proteins functioned
as substrate-specific adaptors. For example, inactivation of L2DTL (DTL;
610617), but not other WDR proteins, prevented CUL4-DDB1-dependent
proteolysis of CDT1 following gamma irradiation. Inactivation of WDR5
(609012) or EED (605984), but not other WDR proteins, altered the
pattern of CUL4-DDB1-dependent histone H3 (see 602810) methylation.
Ohtake et al. (2007) characterized a fat-soluble ligand-dependent
ubiquitin ligase complex in human cell lines, in which dioxin receptor
(AHR; 600253) is integrated as a component of a novel cullin-4B
ubiquitin ligase complex, CUL4B(AHR). Complex assembly and ubiquitin
ligase activity of CUL4B(AHR) in vitro and in vivo are dependent on the
AHR ligand. In the CUL4B(AHR) complex, ligand-activated AHR acts as a
substrate-specific adaptor component that targets sex steroid receptors
for degradation. Ohtake et al. (2007) concluded that their findings
uncovered a function for AHR as an atypical component of the ubiquitin
ligase complex and demonstrated a nongenomic signaling pathway in which
fat-soluble ligands regulate target protein-selective degradation
through a ubiquitin ligase complex.
Kerzendorfer et al. (2010) showed that cells from patients with mental
retardation, macrocephaly, tremor, and peripheral neuropathy (300354)
and CUL4B mutations exhibited sensitivity to camptothecin (CPT),
impaired CPT-induced topoisomerase I (TOP1; 126420) degradation and
ubiquitination, suggesting that TOP1 may be a novel CUL4-dependent
substrate. These cells exhibited increased levels of CPT-induced DNA
breaks, as well as overexpression of the known CUL4-dependent substrates
CDT1 and p21 (CDKN1A; 116899).
MOLECULAR GENETICS
Tarpey et al. (2007) undertook a systematic mutational screen of the X
chromosome in 250 families with multiple members with mental retardation
to provide an alternative strategy to positional cloning. The approach
was not dependent on mapping by genetic linkage and was a direct search
for putative disease-causing mutations. Each family in this screen had a
normal karyotype by conventional 500 G-banding resolution and was
negative for an expansion of the trinucleotide repeat in the FMR1 gene
(309550). They identified 3 truncating, 2 splice site, and 3 missense
variants at conserved amino acids in the CUL4B gene in 8 of the 250
families with X-linked mental retardation. During the adolescence of the
affected subjects, a syndrome emerged with delayed puberty,
hypogonadism, relative macrocephaly, moderate short stature, central
obesity, unprovoked aggressive outbursts, fine intention tremor, pes
cavus, and abnormalities of the toes. This syndrome was first described
by Cabezas et al. (2000) (300354) in a family that was included in the
study of Tarpey et al. (2007); see 300304.0001.
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in
208 families with X-linked mental retardation. They identified 5
nonrecurrent mutations in the CUL4B gene that segregated completely with
mental retardation in the families and were not identified in unaffected
family members. In addition to mental retardation, affected family
members had relative macrocephaly, hypogonadism, central obesity, and
tremor.
In a family reported by Wei et al. (1993) with X-linked mental
retardation in 5 affected males in 4 sibships, Zou et al. (2007)
narrowed the candidate interval on Xq25 and identified a nonsense
mutation in the CUL4B gene (300304.0004). The mutation occurred in exon
9 and truncated the protein before the C-terminal domain. Since the C
terminus is required for the formation of the catalytic core, the
truncated peptide was predicted to have no function. The nonsense
mutation also resulted in nonsense-mediated mRNA decay in patients. In
peripheral leukocytes of obligate carriers, a strong selection against
cells expressing the mutant allele resulted in an extremely skewed
X-chromosome inactivation pattern. The findings pointed to the
functional significance of CUL4B in cognition and in other aspects of
human development. Protein ubiquitination regulates the functions of a
broad spectrum of protein substrates in diverse cellular pathways. Many
human genetic disorders have been found to be caused by errors in
ubiquitination and proteasomal degradation (Jiang and Beaudet, 2004).
For example, lack of expression of UBE3A (601623), a gene that encodes
an E3 ubiquitin-protein ligase, causes Angelman syndrome (105830), which
is characterized by mental retardation, ataxia, absence of speech, and
other features. Opitz syndrome (300000), which is associated with
midline abnormalities--such as cleft lip, laryngeal cleft, heart
defects, and hypospadias--and with mental retardation, is caused by an
impairment of the E3 ubiquitin ligase activity of the MID1 protein
(300552). UBE2A (312810), a gene encoding ubiquitin-conjugating enzyme
E2, has been identified to be the cause of a type of syndromic XLMR
(312180). These findings suggested that ubiquitylation is critical in
cognition as well as other aspects of human development.
In a patient with X-linked mental retardation with relative
macrocephaly, short stature, lack of speech development, hypogonadism,
and abnormal gait, Isidor et al. (2010) identified a 60-kb de novo
deletion at chromosome Xq24 that encompassed the 3-prime region of the
CUL4B gene and the MCTS1 gene (300587). Isidor et al. (2010) concluded
that the deletion would result in premature termination and
nonsense-mediated mRNA decay of CUL4B.
Ravn et al. (2012) identified a maternally inherited 28-kb deletion at
Xq24 in a pair of male monozygotic twins with moderate mental
retardation and pronounced language deficit, short stature, truncal
obesity, relative macrocephaly, characteristic facial dysmorphism,
tremor, and seizures. Using quantitative PCR, Ravn et al. (2012) mapped
the proximal breakpoint within intron 4 of CUL4B and the distal
breakpoint 1,000 bp downstream of the 3-prime UTR. X-inactivation
studies in the unaffected mother revealed an extremely skewed
X-inactivation pattern, consistent with her being an unaffected carrier.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
CUL4B, ARG572CYS
In a family with X-linked mental retardation with short stature,
hypogonadism, and abnormal gait (300354), Tarpey et al. (2007) described
a 1714C-T transition in exon 14 of the CUL4B gene, giving rise to an
arg572-to-cys (R572C) amino acid substitution. Residue R572 is highly
conserved throughout evolution and is located within the cullin domain,
and the arginine-to-cysteine change is a nonconservative substitution.
This was the family originally reported by Cabezas et al. (2000) and
comprised 6 affected individuals in 2 generations and 4 sibships
connected through carrier females.
.0002
MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
CUL4B, ARG388TER
In a family in which 3 males in 2 sibships in 2 generations with
syndromic X-linked mental retardation (300354), Tarpey et al. (2007)
described an 1162C-T transition in exon 9 of the CUL4B gene that caused
an arg388-to-ter (R388X) mutation.
In a Chinese family originally reported by Wei et al. (1993), Zou et al.
(2007) identified a nonsense mutation in the CUL4B gene as the cause of
a syndromic form of X-linked mental retardation. All affected members in
this family had a R388X substitution, which Zou et al. (2007) stated
resulted from a 1564C-T transition in exon 9 (a different numbering
system was used). The mutation rendered the peptide completely devoid of
the C-terminal catalytic domain. Mutant mRNA was degraded by
nonsense-mediated decay (NMD).
.0003
MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
CUL4B, IVS6, A-G, -2
In a family in which 3 brothers had X-linked mental retardation with
short stature, hypogonadism, and abnormal gait (300354), Tarpey et al.
(2007) found a splice acceptor site mutation leading to premature
termination of the CUL4B protein: 901-2A-G. To investigate the effect of
this variant on splicing, CUL4B exons 6 through 11 were amplified.
Sequence analysis demonstrated that the mutated exon 7 splice acceptor
site is ignored, with the result that exon 7 (74 bp) was excluded from
the mature transcript. Removal of exon 7 resulted in a translational
frameshift, with the inclusion of 7 novel amino acids and a premature
termination at codon 308.
*FIELD* RF
1. Cabezas, D. A.; Slaugh, R.; Abidi, F.; Arena, J. F.; Stevenson,
R. E.; Schwartz, C. E.; Lubs, H. A.: A new X linked mental retardation
(XLMR) syndrome with short stature, small testes, muscle wasting,
and tremor localises to Xq24-q25. J. Med. Genet. 37: 663-668, 2000.
2. Higa, L. A.; Wu, M.; Ye, T.; Kobayashi, R.; Sun, H.; Zhang, H.
: CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins
and regulates histone methylation. Nature Cell Biol. 8: 1277-1283,
2006.
3. Ishikawa, K.; Nagase, T.; Suyama, M.; Miyajima, N.; Tanaka, A.;
Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the coding sequences
of unidentified human genes. X. The complete sequences of 100 new
cDNA clones from brain which can code for large proteins in vitro. DNA
Res. 5: 169-176, 1998.
4. Isidor, B.; Pichon, O.; Baron, S.; David, A.; Le Caignec, C.:
Deletion of the CUL4B gene in a boy with mental retardation, minor
facial anomalies, short stature, hypogonadism, and ataxia. Am. J.
Med. Genet. 152A: 175-180, 2010.
5. Jiang, Y. H.; Beaudet, A. L.: Human disorders of ubiquitination
and proteasomal degradation. Curr. Opin. Pediat. 16: 419-426, 2004.
6. Kerzendorfer, C.; Whibley, A.; Carpenter, G.; Outwin, E.; Chiang,
S.-C.; Turner, G.; Schwartz, C.; El-Khamisy, S.; Raymond, F. L.; O'Driscoll,
M.: Mutations in Cullin 4B result in a human syndrome associated
with increased camptothecin-induced topoisomerase I-dependent DNA
breaks. Hum. Molec. Genet. 19: 1324-1334, 2010.
7. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
8. Ohtake, F.; Baba, A.; Takada, I.; Okada, M.; Iwasaki, K.; Miki,
H.; Takahashi, S.; Kouzmenko, A.; Nohara, K.; Chiba, T.; Fujii-Kuriyama,
Y.; Kato, S.: Dioxin receptor is a ligand-dependent E3 ubiquitin
ligase. Nature 446: 562-566, 2007.
9. Rasooly, R. S.: Personal Communication. Baltimore, Md. 9/29/1998.
10. Ravn, K.; Lindquist, S. G.; Nielsen, K.; Dahm, T. L.; Tumer, Z.
: Deletion of CUL4B leads to concordant phenotype in a monozygotic
twin pair. (Letter) Clin. Genet. 82: 292-294, 2012.
11. Tarpey, P. S.; Raymond, F. L.; O'Meara, S.; Edkins, S.; Teague,
J.; Butler, A.; Dicks, E.; Stevens, C.; Tofts, C.; Avis, T.; Barthorpe,
S.; Buck, G.: and 41 others: Mutations in CUL4B, which encodes
a ubiquitin E3 ligase subunit, cause an X-linked mental retardation
syndrome associated with aggressive outbursts, seizures, relative
macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am.
J. Hum. Genet. 80: 345-352, 2007.
12. Tarpey, P. S.; Smith, R.; Pleasance, E.; Whibley, A.; Edkins,
S.; Hardy, C.; O'Meara, S.; Latimer, C.; Dicks, E.; Menzies, A.; Stephens,
P.; Blow, M.; and 67 others: A systematic, large-scale resequencing
screen of X-chromosome coding exons in mental retardation. Nature
Genet. 41: 535-543, 2009.
13. Wei, J.; Chen, B.; Jiang, Y.; Yang, Y.; Guo, Y.: Smith-Fineman-Myers
syndrome: report on a large family. Am. J. Med. Genet. 47: 307-311,
1993.
14. Zhong, W.; Feng, H.; Santiago, F. E.; Kipreos, E. T.: CUL-4 ubiquitin
ligase maintains genome stability by restraining DNA-replication licensing. Nature 423:
885-889, 2003.
15. Zou, Y.; Liu, Q.; Chen, B.; Zhang, X.; Guo, C.; Zhou, H.; Li,
J.; Gao, G.; Guo, Y.; Yan, C.; Wei, J.; Shao, C.; Gong, Y.: Mutation
in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex,
causes X-linked mental retardation. Am. J. Hum. Genet. 80: 561-566,
2007.
*FIELD* CN
Jill A. Fahrner - updated: 4/5/2013
Patricia A. Hartz - updated: 3/5/2013
George E. Tiller - updated: 11/14/2011
Cassandra L. Kniffin - updated: 1/5/2011
Ada Hamosh - updated: 10/1/2009
Ada Hamosh - updated: 4/11/2007
Victor A. McKusick - updated: 2/15/2007
Victor A. McKusick - updated: 1/18/2007
Ada Hamosh - updated: 7/8/2003
*FIELD* CD
Victor A. McKusick: 3/13/2001
*FIELD* ED
carol: 09/11/2013
carol: 4/5/2013
mgross: 3/5/2013
carol: 11/17/2011
terry: 11/14/2011
wwang: 1/24/2011
ckniffin: 1/5/2011
alopez: 10/6/2009
terry: 10/1/2009
alopez: 11/29/2007
alopez: 11/21/2007
alopez: 4/12/2007
carol: 4/11/2007
alopez: 2/19/2007
carol: 2/15/2007
alopez: 1/19/2007
terry: 1/18/2007
alopez: 7/9/2003
terry: 7/8/2003
carol: 3/13/2001
*RECORD*
*FIELD* NO
300304
*FIELD* TI
*300304 CULLIN 4B; CUL4B
;;KIAA0695
*FIELD* TX
CLONING
Kipreos et al. (1996) identified the cullin gene family, which includes
read moreat least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae.
Human CUL4A (603137) and CUL4B are orthologs of nematode cul4. The
partial C-terminal amino acid sequences of CUL4A and CUL4B share 88%
identity. Rasooly (1998) found that a brain cDNA isolated by Ishikawa et
al. (1998), KIAA0695, was 99% identical to CUL4B. Using RT-PCR, Ishikawa
et al. (1998) determined that KIAA0695 is expressed ubiquitously.
Tarpey et al. (2007) reported that the CUL4B gene encodes a protein of
913 amino acids. The cullin domain is located between amino acid
residues 217 and 815 and is characterized a by C-terminal globular
domain (cullin homology domain) and a series of N-terminal repeats
(cullin repeats).
GENE STRUCTURE
The CUL4B gene contains 22 exons (Tarpey et al., 2007).
MAPPING
Although Ishikawa et al. (1998) mapped the KIAA0695 gene to human
chromosome 10, Rasooly (1998) noted the presence of sequences in GenBank
(GENBANK AC002476) identical to CUL4B within a cloned region in Xq23.
Tarpey et al. (2007) placed the CUL4B gene in Xq24.
GENE FUNCTION
Zhong et al. (2003) showed that the CUL4 ubiquitin ligase temporally
restricts DNA replication licensing in Caenorhabditis elegans.
Inactivation of CUL4 causes massive DNA rereplication, producing cells
with up to 100C DNA content. The C. elegans ortholog of the
replication-licensing factor CDT1 (605525) is required for DNA
replication. C. elegans CDT1 is present in G1-phase nuclei but
disappears as cells enter S phase. In cells lacking CUL4, CDT1 levels
failed to decrease during S phase and instead remained constant in the
rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the
CUL4 rereplication phenotype. Zhong et al. (2003) proposed that CUL4
prevents aberrant reinitiation of DNA replication, at least in part, by
facilitating the degradation of CDT1.
By mass spectrometric analysis, Higa et al. (2006) identified over 20
WD40 repeat-containing (WDR) proteins that interacted with the CUL4-DDB1
(600045)-ROC1 (RBX1; 603814) complex. Sequence alignment revealed that
most of the interacting WDR proteins had a centrally positioned WDxR/K
submotif. Knockdown studies suggested that the WDR proteins functioned
as substrate-specific adaptors. For example, inactivation of L2DTL (DTL;
610617), but not other WDR proteins, prevented CUL4-DDB1-dependent
proteolysis of CDT1 following gamma irradiation. Inactivation of WDR5
(609012) or EED (605984), but not other WDR proteins, altered the
pattern of CUL4-DDB1-dependent histone H3 (see 602810) methylation.
Ohtake et al. (2007) characterized a fat-soluble ligand-dependent
ubiquitin ligase complex in human cell lines, in which dioxin receptor
(AHR; 600253) is integrated as a component of a novel cullin-4B
ubiquitin ligase complex, CUL4B(AHR). Complex assembly and ubiquitin
ligase activity of CUL4B(AHR) in vitro and in vivo are dependent on the
AHR ligand. In the CUL4B(AHR) complex, ligand-activated AHR acts as a
substrate-specific adaptor component that targets sex steroid receptors
for degradation. Ohtake et al. (2007) concluded that their findings
uncovered a function for AHR as an atypical component of the ubiquitin
ligase complex and demonstrated a nongenomic signaling pathway in which
fat-soluble ligands regulate target protein-selective degradation
through a ubiquitin ligase complex.
Kerzendorfer et al. (2010) showed that cells from patients with mental
retardation, macrocephaly, tremor, and peripheral neuropathy (300354)
and CUL4B mutations exhibited sensitivity to camptothecin (CPT),
impaired CPT-induced topoisomerase I (TOP1; 126420) degradation and
ubiquitination, suggesting that TOP1 may be a novel CUL4-dependent
substrate. These cells exhibited increased levels of CPT-induced DNA
breaks, as well as overexpression of the known CUL4-dependent substrates
CDT1 and p21 (CDKN1A; 116899).
MOLECULAR GENETICS
Tarpey et al. (2007) undertook a systematic mutational screen of the X
chromosome in 250 families with multiple members with mental retardation
to provide an alternative strategy to positional cloning. The approach
was not dependent on mapping by genetic linkage and was a direct search
for putative disease-causing mutations. Each family in this screen had a
normal karyotype by conventional 500 G-banding resolution and was
negative for an expansion of the trinucleotide repeat in the FMR1 gene
(309550). They identified 3 truncating, 2 splice site, and 3 missense
variants at conserved amino acids in the CUL4B gene in 8 of the 250
families with X-linked mental retardation. During the adolescence of the
affected subjects, a syndrome emerged with delayed puberty,
hypogonadism, relative macrocephaly, moderate short stature, central
obesity, unprovoked aggressive outbursts, fine intention tremor, pes
cavus, and abnormalities of the toes. This syndrome was first described
by Cabezas et al. (2000) (300354) in a family that was included in the
study of Tarpey et al. (2007); see 300304.0001.
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in
208 families with X-linked mental retardation. They identified 5
nonrecurrent mutations in the CUL4B gene that segregated completely with
mental retardation in the families and were not identified in unaffected
family members. In addition to mental retardation, affected family
members had relative macrocephaly, hypogonadism, central obesity, and
tremor.
In a family reported by Wei et al. (1993) with X-linked mental
retardation in 5 affected males in 4 sibships, Zou et al. (2007)
narrowed the candidate interval on Xq25 and identified a nonsense
mutation in the CUL4B gene (300304.0004). The mutation occurred in exon
9 and truncated the protein before the C-terminal domain. Since the C
terminus is required for the formation of the catalytic core, the
truncated peptide was predicted to have no function. The nonsense
mutation also resulted in nonsense-mediated mRNA decay in patients. In
peripheral leukocytes of obligate carriers, a strong selection against
cells expressing the mutant allele resulted in an extremely skewed
X-chromosome inactivation pattern. The findings pointed to the
functional significance of CUL4B in cognition and in other aspects of
human development. Protein ubiquitination regulates the functions of a
broad spectrum of protein substrates in diverse cellular pathways. Many
human genetic disorders have been found to be caused by errors in
ubiquitination and proteasomal degradation (Jiang and Beaudet, 2004).
For example, lack of expression of UBE3A (601623), a gene that encodes
an E3 ubiquitin-protein ligase, causes Angelman syndrome (105830), which
is characterized by mental retardation, ataxia, absence of speech, and
other features. Opitz syndrome (300000), which is associated with
midline abnormalities--such as cleft lip, laryngeal cleft, heart
defects, and hypospadias--and with mental retardation, is caused by an
impairment of the E3 ubiquitin ligase activity of the MID1 protein
(300552). UBE2A (312810), a gene encoding ubiquitin-conjugating enzyme
E2, has been identified to be the cause of a type of syndromic XLMR
(312180). These findings suggested that ubiquitylation is critical in
cognition as well as other aspects of human development.
In a patient with X-linked mental retardation with relative
macrocephaly, short stature, lack of speech development, hypogonadism,
and abnormal gait, Isidor et al. (2010) identified a 60-kb de novo
deletion at chromosome Xq24 that encompassed the 3-prime region of the
CUL4B gene and the MCTS1 gene (300587). Isidor et al. (2010) concluded
that the deletion would result in premature termination and
nonsense-mediated mRNA decay of CUL4B.
Ravn et al. (2012) identified a maternally inherited 28-kb deletion at
Xq24 in a pair of male monozygotic twins with moderate mental
retardation and pronounced language deficit, short stature, truncal
obesity, relative macrocephaly, characteristic facial dysmorphism,
tremor, and seizures. Using quantitative PCR, Ravn et al. (2012) mapped
the proximal breakpoint within intron 4 of CUL4B and the distal
breakpoint 1,000 bp downstream of the 3-prime UTR. X-inactivation
studies in the unaffected mother revealed an extremely skewed
X-inactivation pattern, consistent with her being an unaffected carrier.
*FIELD* AV
.0001
MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
CUL4B, ARG572CYS
In a family with X-linked mental retardation with short stature,
hypogonadism, and abnormal gait (300354), Tarpey et al. (2007) described
a 1714C-T transition in exon 14 of the CUL4B gene, giving rise to an
arg572-to-cys (R572C) amino acid substitution. Residue R572 is highly
conserved throughout evolution and is located within the cullin domain,
and the arginine-to-cysteine change is a nonconservative substitution.
This was the family originally reported by Cabezas et al. (2000) and
comprised 6 affected individuals in 2 generations and 4 sibships
connected through carrier females.
.0002
MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
CUL4B, ARG388TER
In a family in which 3 males in 2 sibships in 2 generations with
syndromic X-linked mental retardation (300354), Tarpey et al. (2007)
described an 1162C-T transition in exon 9 of the CUL4B gene that caused
an arg388-to-ter (R388X) mutation.
In a Chinese family originally reported by Wei et al. (1993), Zou et al.
(2007) identified a nonsense mutation in the CUL4B gene as the cause of
a syndromic form of X-linked mental retardation. All affected members in
this family had a R388X substitution, which Zou et al. (2007) stated
resulted from a 1564C-T transition in exon 9 (a different numbering
system was used). The mutation rendered the peptide completely devoid of
the C-terminal catalytic domain. Mutant mRNA was degraded by
nonsense-mediated decay (NMD).
.0003
MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
CUL4B, IVS6, A-G, -2
In a family in which 3 brothers had X-linked mental retardation with
short stature, hypogonadism, and abnormal gait (300354), Tarpey et al.
(2007) found a splice acceptor site mutation leading to premature
termination of the CUL4B protein: 901-2A-G. To investigate the effect of
this variant on splicing, CUL4B exons 6 through 11 were amplified.
Sequence analysis demonstrated that the mutated exon 7 splice acceptor
site is ignored, with the result that exon 7 (74 bp) was excluded from
the mature transcript. Removal of exon 7 resulted in a translational
frameshift, with the inclusion of 7 novel amino acids and a premature
termination at codon 308.
*FIELD* RF
1. Cabezas, D. A.; Slaugh, R.; Abidi, F.; Arena, J. F.; Stevenson,
R. E.; Schwartz, C. E.; Lubs, H. A.: A new X linked mental retardation
(XLMR) syndrome with short stature, small testes, muscle wasting,
and tremor localises to Xq24-q25. J. Med. Genet. 37: 663-668, 2000.
2. Higa, L. A.; Wu, M.; Ye, T.; Kobayashi, R.; Sun, H.; Zhang, H.
: CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins
and regulates histone methylation. Nature Cell Biol. 8: 1277-1283,
2006.
3. Ishikawa, K.; Nagase, T.; Suyama, M.; Miyajima, N.; Tanaka, A.;
Kotani, H.; Nomura, N.; Ohara, O.: Prediction of the coding sequences
of unidentified human genes. X. The complete sequences of 100 new
cDNA clones from brain which can code for large proteins in vitro. DNA
Res. 5: 169-176, 1998.
4. Isidor, B.; Pichon, O.; Baron, S.; David, A.; Le Caignec, C.:
Deletion of the CUL4B gene in a boy with mental retardation, minor
facial anomalies, short stature, hypogonadism, and ataxia. Am. J.
Med. Genet. 152A: 175-180, 2010.
5. Jiang, Y. H.; Beaudet, A. L.: Human disorders of ubiquitination
and proteasomal degradation. Curr. Opin. Pediat. 16: 419-426, 2004.
6. Kerzendorfer, C.; Whibley, A.; Carpenter, G.; Outwin, E.; Chiang,
S.-C.; Turner, G.; Schwartz, C.; El-Khamisy, S.; Raymond, F. L.; O'Driscoll,
M.: Mutations in Cullin 4B result in a human syndrome associated
with increased camptothecin-induced topoisomerase I-dependent DNA
breaks. Hum. Molec. Genet. 19: 1324-1334, 2010.
7. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
8. Ohtake, F.; Baba, A.; Takada, I.; Okada, M.; Iwasaki, K.; Miki,
H.; Takahashi, S.; Kouzmenko, A.; Nohara, K.; Chiba, T.; Fujii-Kuriyama,
Y.; Kato, S.: Dioxin receptor is a ligand-dependent E3 ubiquitin
ligase. Nature 446: 562-566, 2007.
9. Rasooly, R. S.: Personal Communication. Baltimore, Md. 9/29/1998.
10. Ravn, K.; Lindquist, S. G.; Nielsen, K.; Dahm, T. L.; Tumer, Z.
: Deletion of CUL4B leads to concordant phenotype in a monozygotic
twin pair. (Letter) Clin. Genet. 82: 292-294, 2012.
11. Tarpey, P. S.; Raymond, F. L.; O'Meara, S.; Edkins, S.; Teague,
J.; Butler, A.; Dicks, E.; Stevens, C.; Tofts, C.; Avis, T.; Barthorpe,
S.; Buck, G.: and 41 others: Mutations in CUL4B, which encodes
a ubiquitin E3 ligase subunit, cause an X-linked mental retardation
syndrome associated with aggressive outbursts, seizures, relative
macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am.
J. Hum. Genet. 80: 345-352, 2007.
12. Tarpey, P. S.; Smith, R.; Pleasance, E.; Whibley, A.; Edkins,
S.; Hardy, C.; O'Meara, S.; Latimer, C.; Dicks, E.; Menzies, A.; Stephens,
P.; Blow, M.; and 67 others: A systematic, large-scale resequencing
screen of X-chromosome coding exons in mental retardation. Nature
Genet. 41: 535-543, 2009.
13. Wei, J.; Chen, B.; Jiang, Y.; Yang, Y.; Guo, Y.: Smith-Fineman-Myers
syndrome: report on a large family. Am. J. Med. Genet. 47: 307-311,
1993.
14. Zhong, W.; Feng, H.; Santiago, F. E.; Kipreos, E. T.: CUL-4 ubiquitin
ligase maintains genome stability by restraining DNA-replication licensing. Nature 423:
885-889, 2003.
15. Zou, Y.; Liu, Q.; Chen, B.; Zhang, X.; Guo, C.; Zhou, H.; Li,
J.; Gao, G.; Guo, Y.; Yan, C.; Wei, J.; Shao, C.; Gong, Y.: Mutation
in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex,
causes X-linked mental retardation. Am. J. Hum. Genet. 80: 561-566,
2007.
*FIELD* CN
Jill A. Fahrner - updated: 4/5/2013
Patricia A. Hartz - updated: 3/5/2013
George E. Tiller - updated: 11/14/2011
Cassandra L. Kniffin - updated: 1/5/2011
Ada Hamosh - updated: 10/1/2009
Ada Hamosh - updated: 4/11/2007
Victor A. McKusick - updated: 2/15/2007
Victor A. McKusick - updated: 1/18/2007
Ada Hamosh - updated: 7/8/2003
*FIELD* CD
Victor A. McKusick: 3/13/2001
*FIELD* ED
carol: 09/11/2013
carol: 4/5/2013
mgross: 3/5/2013
carol: 11/17/2011
terry: 11/14/2011
wwang: 1/24/2011
ckniffin: 1/5/2011
alopez: 10/6/2009
terry: 10/1/2009
alopez: 11/29/2007
alopez: 11/21/2007
alopez: 4/12/2007
carol: 4/11/2007
alopez: 2/19/2007
carol: 2/15/2007
alopez: 1/19/2007
terry: 1/18/2007
alopez: 7/9/2003
terry: 7/8/2003
carol: 3/13/2001
MIM
300354
*RECORD*
*FIELD* NO
300354
*FIELD* TI
#300354 MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
read more;;MENTAL RETARDATION, X-LINKED, SYNDROMIC 15; MRXS15;;
CABEZAS X-LINKED MENTAL RETARDATION SYNDROME; MRXSC;;
CABEZAS SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of syndromic X-linked mental retardation is caused by mutation in
the CUL4B gene (300304).
DESCRIPTION
This form of syndromic X-linked mental retardation is characterized
primarily by short stature, hypogonadism, and abnormal gait, with other
more variable features such as speech delay, prominent lower lip, and
tremor (Cabezas et al., 2000).
CLINICAL FEATURES
In a population survey for common hereditary diseases conducted in China
in 1990, Wei et al. (1993) identified a family with X-linked mental
retardation in 5 affected males in 4 sibships. The distinguishing
manifestations were short stature, patulous lips, difficulty in speech,
short thumbs and little fingers with adduction, hypotonia at age less
than 10 years, and later hypertonia, restlessness, and seizures. Other
features included pes planus, and 2 had small testes, with delayed sex
development in 1. IQ ranged from 40 through 57. Obligate carrier females
were clinically normal except for rather large hands with deep palmar
and finger creases with rhagades. The disorder was initially classified
as Smith-Fineman-Myers syndrome (SFMS; 309580), based on mild facial
dysmorphisms, such as microcephaly, hypertelorism, micrognathia, and
macrostomia. However, on reexamination of this family, Zou et al. (2007)
noted that no remarkable facial features were present; in particular,
the small palpebral fissures, flat nasal bridge, micrognathia, and
hypertelorism characteristic of SFMS were not obvious. However, several
other physical features were distinct, including short stature,
brachydactyly, macroglossia, and a unique gait, with toes pointing
inwards.
Cabezas et al. (2000) reported a large family in which 7 males with
mental retardation were identified, with transmission from 5 normal or
minimally affected female carriers and an absence of male-to-male
transmission. Characteristic clinical features included short stature,
prominent lower lip, small testes, muscle wasting in lower legs,
kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased
fine motor coordination. Affected subjects had impaired speech and
decreased attention span. For the 3 individuals for whom IQ data were
available, scores ranged from 29 to 54; affected males were described as
being retarded by clinical examination and history. One female carrier
was examined and had normal growth and development but had been
evaluated for Tourette syndrome (137580) and had several tics, memory
problems, and learning difficulties. On examination at age 12 years, she
had a thin habitus and a mild tremor in the upper extremities.
Tarpey et al. (2007) discussed the clinical features of the family
described by Cabezas et al. (2000) and 7 additional families. During the
adolescence of affected subjects, a syndrome emerged with delayed
puberty, hypogonadism, relative macrocephaly, moderate short stature,
central obesity, unprovoked aggressive outbursts, fine intention tremor,
pes cavus, and abnormalities of the toes. Seven families were white, and
1 was of Asian descent.
Ravn et al. (2012) described a Danish monozygotic twin pair concordant
for X-linked mental retardation resulting from a deletion encompassing
most of the CUL4B gene. Ravn et al. (2012) found that the twins shared
many of the features in patients previously reported with mutation in
the CUL4B gene, including moderate mental retardation with pronounced
language deficit, short stature, truncal obesity, relative macrocephaly,
characteristic facial dysmorphisms, tremor, and seizures. In addition,
twin A exhibited intrauterine growth retardation, and twin B had
scaphocephaly due to premature fusion of the sagittal suture.
MAPPING
Cabezas et al. (2000) performed linkage analysis on their family with
syndromic X-linked mental retardation and achieved a maximum lod score
of 2.80 at marker DXS1212 and 2.76 at DXS425, within a region defined by
markers DXS424 and DXS1047 (Xq24-q25).
Using linkage analysis, Gong et al. (1999) mapped the phenotype in the
family reported by Wei et al. (1993) to a 20-Mb interval between DXS8064
and DXS8050 on chromosome Xq25. Liu et al. (2002) excluded linkage of
the ATRX gene (300032) at Xq13 to the disorder in this family,
confirming locus heterogeneity for the disorder. Liu et al. (2004)
narrowed the candidate interval to a 10.18-Mb region between XSTR3 and
XSTR4.
PATHOGENESIS
Kerzendorfer et al. (2010) showed that cells from patients with mental
retardation, macrocephaly, tremor, peripheral neuropathy, and CUL4B
mutations exhibited sensitivity to camptothecin (CPT), impaired
CPT-induced topoisomerase I (TOP1; 126420) degradation and
ubiquitination, suggesting that TOP1 may be a novel CUL4-dependent
substrate. These cells exhibited increased levels of CPT-induced DNA
breaks, as well as overexpression of the known CUL4-dependent substrates
CDT1 (605525) and p21 (CDKN1A; 116899).
MOLECULAR GENETICS
By a systematic mutational screen of the X chromosome in 250 families
with multiple members with X-linked mental retardation, Tarpey et al.
(2007) found 8 families who carried mutations in the CUL4B gene (see,
e.g., 300304.0001-300304.0003) on Xq24. One of these was the family
reported by Cabezas et al. (2000). CUL4B is a ubiquitin E3 ligase
subunit implicated in the regulation of several biologic processes, and
CUL4B was the first identified XLMR gene that encodes an E3 ubiquitin
ligase. The relatively high frequency of CUL4B mutations in this series
(8/250) indicated that it is one of the most commonly mutated genes
underlying XLMR and suggested that its introduction into clinical
diagnostics should be a high priority.
In the family reported by Wei et al. (1993), Zou et al. (2007) detected
a nonsense mutation in the CUL4B gene (300304.0004) that rendered the
peptide completely devoid of the C-terminal domain. Mutant mRNA
underwent nonsense-mediated decay (NMD). In peripheral leukocytes of
obligate carriers a strong selection against cells expressing the mutant
allele resulted in an extremely skewed X chromosome inactivation
pattern. These findings pointed to the functional significance of CUL4B
in cognition and in other aspects of human development.
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in
208 families with X-linked mental retardation. They identified 5
nonrecurrent mutations in the CUL4B gene that segregated completely with
mental retardation in the families and were not identified in unaffected
family members. In addition to mental retardation, affected family
members had relative macrocephaly, hypogonadism, central obesity, and
tremor.
CYTOGENETICS
In a patient with X-linked mental retardation with relative
macrocephaly, short stature, lack of speech development, hypogonadism,
and abnormal gait, Isidor et al. (2010) identified a 60-kb de novo
deletion at chromosome Xq24 that encompassed the 3-prime region of the
CUL4B gene and the MCTS1 gene (300587). Isidor et al. (2010) concluded
that the deletion would result in premature termination and
nonsense-mediated mRNA decay of CUL4B.
In a monozygotic twin pair with X-linked mental retardation, Ravn et al.
(2012) identified a 28-kb deletion on the X chromosome, which partially
encompassed the CUL4B gene and which was inherited from the unaffected
mother. Using quantitative PCR, Ravn et al. (2012) mapped the proximal
breakpoint within intron 4 of CUL4B and the distal breakpoint 1,000 bp
downstream of the 3-prime UTR. X-inactivation studies in the unaffected
mother revealed an extremely skewed X-inactivation pattern, consistent
with her being an unaffected carrier.
*FIELD* RF
1. Cabezas, D. A.; Slaugh, R.; Abidi, F.; Arena, J. F.; Stevenson,
R. E.; Schwartz, C. E.; Lubs, H. A.: A new X linked mental retardation
(XLMR) syndrome with short stature, small testes, muscle wasting,
and tremor localises to Xq24-q25. J. Med. Genet. 37: 663-668, 2000.
2. Gong, Y.; Wei, J.; Shao, C.; Guo, Y.; Chen, B.; Guo, C.; Warman,
M.: Mapping of the gene responsible for Smith-Fineman-Myers syndrome
to Xq25. Chinese J. Med. Genet. 16: 277-280, 1999. Note: Article
in Chinese.
3. Isidor, B.; Pichon, O.; Baron, S.; David, A.; Le Caignec, C.:
Deletion of the CUL4B gene in a boy with mental retardation, minor
facial anomalies, short stature, hypogonadism, and ataxia. Am. J.
Med. Genet. 152A: 175-180, 2010.
4. Kerzendorfer, C.; Whibley, A.; Carpenter, G.; Outwin, E.; Chiang,
S.-C.; Turner, G.; Schwartz, C.; El-Khamisy, S.; Raymond, F. L.; O'Driscoll,
M.: Mutations in Cullin 4B result in a human syndrome associated
with increased camptothecin-induced topoisomerase I-dependent DNA
breaks. Hum. Molec. Genet. 19: 1324-1334, 2010.
5. Liu, Q.; Gong, Y.; Chen, B.; Guo, C.; Li, J.; Guo, Y.: [Linkage
analysis of X-linked nuclear protein gene in Smith-Fineman-Myers syndrome.] Chinese
J. Med. Genet. 19: 22-25, 2002. Note: Article in Chinese.
6. Liu, Q. J.; Gong, Y. Q.; Li, J. X.; Zhang, X. Y.; Gao, G. M.; Guo,
Y. S.: [Fine mapping of Smith-Fineman-Myers syndrome and exclusion
of GPC3, GPCR2, MST4 and GLUD2 as candidate genes.] Chinese J. Med.
Genet. 21: 198-202, 2004. Note: Article in Chinese.
7. Ravn, K.; Lindquist, S. G.; Nielsen, K.; Dahm, T. L.; Tumer, Z.
: Deletion of CUL4B leads to concordant phenotype in a monozygotic
twin pair. (Letter) Clin. Genet. 82: 292-294, 2012.
8. Tarpey, P. S.; Raymond, F. L.; O'Meara, S.; Edkins, S.; Teague,
J.; Butler, A.; Dicks, E.; Stevens, C.; Tofts, C.; Avis, T.; Barthorpe,
S.; Buck, G.: and 41 others: Mutations in CUL4B, which encodes
a ubiquitin E3 ligase subunit, cause an X-linked mental retardation
syndrome associated with aggressive outbursts, seizures, relative
macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am.
J. Hum. Genet. 80: 345-352, 2007.
9. Tarpey, P. S.; Smith, R.; Pleasance, E.; Whibley, A.; Edkins, S.;
Hardy, C.; O'Meara, S.; Latimer, C.; Dicks, E.; Menzies, A.; Stephens,
P.; Blow, M.; and 67 others: A systematic, large-scale resequencing
screen of X-chromosome coding exons in mental retardation. Nature
Genet. 41: 535-543, 2009.
10. Wei, J.; Chen, B.; Jiang, Y.; Yang, Y.; Guo, Y.: Smith-Fineman-Myers
syndrome: report on a large family. Am. J. Med. Genet. 47: 307-311,
1993.
11. Zou, Y.; Liu, Q.; Chen, B.; Zhang, X.; Guo, C.; Zhou, H.; Li,
J.; Gao, G.; Guo, Y.; Yan, C.; Wei, J.; Shao, C.; Gong, Y.: Mutation
in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex,
causes X-linked mental retardation. Am. J. Hum. Genet. 80: 561-566,
2007.
*FIELD* CS
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Short stature (5th percentile);
[Weight];
Central obesity;
Birthweight (<10th percentile)
HEAD AND NECK:
[Head];
Macrocephaly, relative;
[Mouth];
Prominent lower lip;
Macroglossia
CHEST:
[Breasts];
Gynecomastia
GENITOURINARY:
[External genitalia, male];
Hypospadias;
Small penis;
[Internal genitalia, male];
Cryptorchidism;
Small testes
SKELETAL:
Joint laxity;
[Spine];
Kyphosis;
[Hands];
Brachydactyly (in 1 family);
[Feet];
Small feet;
Pes cavus;
Pes planus;
Wide sandal gap
SKIN, NAILS, HAIR:
[Skin];
Striae
MUSCLE, SOFT TISSUE:
Wasted lower leg muscles
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Speech delay, severe;
Lack of speech development;
Tremor;
Decreased fine motor coordination;
Seizures (onset <2 years);
Abnormal gait;
Ataxic gait;
[Behavioral/psychiatric manifestations];
Aggressive outbursts;
Hyperactivity;
Mood swings;
Decreased attention span
VOICE:
Impaired/absent speech
ENDOCRINE FEATURES:
Delayed puberty;
Hypogonadism
MOLECULAR BASIS:
Caused by mutation in the cullin 4B gene (CUL4B, 300304.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/5/2011
*FIELD* CD
Kelly A. Przylepa: 3/6/2008
*FIELD* ED
joanna: 07/02/2013
joanna: 7/17/2012
ckniffin: 1/5/2011
joanna: 3/6/2008
alopez: 8/15/2001
*FIELD* CN
Jill A. Fahrner - updated: 4/5/2013
George E. Tiller - updated: 11/14/2011
Cassandra L. Kniffin - updated: 1/5/2011
Victor A. McKusick - updated: 1/18/2007
*FIELD* CD
Michael J. Wright: 8/15/2001
*FIELD* ED
carol: 09/09/2013
carol: 4/5/2013
carol: 11/17/2011
terry: 11/14/2011
carol: 10/26/2011
wwang: 1/24/2011
ckniffin: 1/5/2011
carol: 11/30/2010
alopez: 10/6/2009
alopez: 1/19/2007
terry: 1/18/2007
ckniffin: 7/20/2005
alopez: 8/15/2001
*RECORD*
*FIELD* NO
300354
*FIELD* TI
#300354 MENTAL RETARDATION, X-LINKED, WITH SHORT STATURE, HYPOGONADISM, AND
ABNORMAL GAIT
read more;;MENTAL RETARDATION, X-LINKED, SYNDROMIC 15; MRXS15;;
CABEZAS X-LINKED MENTAL RETARDATION SYNDROME; MRXSC;;
CABEZAS SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
form of syndromic X-linked mental retardation is caused by mutation in
the CUL4B gene (300304).
DESCRIPTION
This form of syndromic X-linked mental retardation is characterized
primarily by short stature, hypogonadism, and abnormal gait, with other
more variable features such as speech delay, prominent lower lip, and
tremor (Cabezas et al., 2000).
CLINICAL FEATURES
In a population survey for common hereditary diseases conducted in China
in 1990, Wei et al. (1993) identified a family with X-linked mental
retardation in 5 affected males in 4 sibships. The distinguishing
manifestations were short stature, patulous lips, difficulty in speech,
short thumbs and little fingers with adduction, hypotonia at age less
than 10 years, and later hypertonia, restlessness, and seizures. Other
features included pes planus, and 2 had small testes, with delayed sex
development in 1. IQ ranged from 40 through 57. Obligate carrier females
were clinically normal except for rather large hands with deep palmar
and finger creases with rhagades. The disorder was initially classified
as Smith-Fineman-Myers syndrome (SFMS; 309580), based on mild facial
dysmorphisms, such as microcephaly, hypertelorism, micrognathia, and
macrostomia. However, on reexamination of this family, Zou et al. (2007)
noted that no remarkable facial features were present; in particular,
the small palpebral fissures, flat nasal bridge, micrognathia, and
hypertelorism characteristic of SFMS were not obvious. However, several
other physical features were distinct, including short stature,
brachydactyly, macroglossia, and a unique gait, with toes pointing
inwards.
Cabezas et al. (2000) reported a large family in which 7 males with
mental retardation were identified, with transmission from 5 normal or
minimally affected female carriers and an absence of male-to-male
transmission. Characteristic clinical features included short stature,
prominent lower lip, small testes, muscle wasting in lower legs,
kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased
fine motor coordination. Affected subjects had impaired speech and
decreased attention span. For the 3 individuals for whom IQ data were
available, scores ranged from 29 to 54; affected males were described as
being retarded by clinical examination and history. One female carrier
was examined and had normal growth and development but had been
evaluated for Tourette syndrome (137580) and had several tics, memory
problems, and learning difficulties. On examination at age 12 years, she
had a thin habitus and a mild tremor in the upper extremities.
Tarpey et al. (2007) discussed the clinical features of the family
described by Cabezas et al. (2000) and 7 additional families. During the
adolescence of affected subjects, a syndrome emerged with delayed
puberty, hypogonadism, relative macrocephaly, moderate short stature,
central obesity, unprovoked aggressive outbursts, fine intention tremor,
pes cavus, and abnormalities of the toes. Seven families were white, and
1 was of Asian descent.
Ravn et al. (2012) described a Danish monozygotic twin pair concordant
for X-linked mental retardation resulting from a deletion encompassing
most of the CUL4B gene. Ravn et al. (2012) found that the twins shared
many of the features in patients previously reported with mutation in
the CUL4B gene, including moderate mental retardation with pronounced
language deficit, short stature, truncal obesity, relative macrocephaly,
characteristic facial dysmorphisms, tremor, and seizures. In addition,
twin A exhibited intrauterine growth retardation, and twin B had
scaphocephaly due to premature fusion of the sagittal suture.
MAPPING
Cabezas et al. (2000) performed linkage analysis on their family with
syndromic X-linked mental retardation and achieved a maximum lod score
of 2.80 at marker DXS1212 and 2.76 at DXS425, within a region defined by
markers DXS424 and DXS1047 (Xq24-q25).
Using linkage analysis, Gong et al. (1999) mapped the phenotype in the
family reported by Wei et al. (1993) to a 20-Mb interval between DXS8064
and DXS8050 on chromosome Xq25. Liu et al. (2002) excluded linkage of
the ATRX gene (300032) at Xq13 to the disorder in this family,
confirming locus heterogeneity for the disorder. Liu et al. (2004)
narrowed the candidate interval to a 10.18-Mb region between XSTR3 and
XSTR4.
PATHOGENESIS
Kerzendorfer et al. (2010) showed that cells from patients with mental
retardation, macrocephaly, tremor, peripheral neuropathy, and CUL4B
mutations exhibited sensitivity to camptothecin (CPT), impaired
CPT-induced topoisomerase I (TOP1; 126420) degradation and
ubiquitination, suggesting that TOP1 may be a novel CUL4-dependent
substrate. These cells exhibited increased levels of CPT-induced DNA
breaks, as well as overexpression of the known CUL4-dependent substrates
CDT1 (605525) and p21 (CDKN1A; 116899).
MOLECULAR GENETICS
By a systematic mutational screen of the X chromosome in 250 families
with multiple members with X-linked mental retardation, Tarpey et al.
(2007) found 8 families who carried mutations in the CUL4B gene (see,
e.g., 300304.0001-300304.0003) on Xq24. One of these was the family
reported by Cabezas et al. (2000). CUL4B is a ubiquitin E3 ligase
subunit implicated in the regulation of several biologic processes, and
CUL4B was the first identified XLMR gene that encodes an E3 ubiquitin
ligase. The relatively high frequency of CUL4B mutations in this series
(8/250) indicated that it is one of the most commonly mutated genes
underlying XLMR and suggested that its introduction into clinical
diagnostics should be a high priority.
In the family reported by Wei et al. (1993), Zou et al. (2007) detected
a nonsense mutation in the CUL4B gene (300304.0004) that rendered the
peptide completely devoid of the C-terminal domain. Mutant mRNA
underwent nonsense-mediated decay (NMD). In peripheral leukocytes of
obligate carriers a strong selection against cells expressing the mutant
allele resulted in an extremely skewed X chromosome inactivation
pattern. These findings pointed to the functional significance of CUL4B
in cognition and in other aspects of human development.
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in
208 families with X-linked mental retardation. They identified 5
nonrecurrent mutations in the CUL4B gene that segregated completely with
mental retardation in the families and were not identified in unaffected
family members. In addition to mental retardation, affected family
members had relative macrocephaly, hypogonadism, central obesity, and
tremor.
CYTOGENETICS
In a patient with X-linked mental retardation with relative
macrocephaly, short stature, lack of speech development, hypogonadism,
and abnormal gait, Isidor et al. (2010) identified a 60-kb de novo
deletion at chromosome Xq24 that encompassed the 3-prime region of the
CUL4B gene and the MCTS1 gene (300587). Isidor et al. (2010) concluded
that the deletion would result in premature termination and
nonsense-mediated mRNA decay of CUL4B.
In a monozygotic twin pair with X-linked mental retardation, Ravn et al.
(2012) identified a 28-kb deletion on the X chromosome, which partially
encompassed the CUL4B gene and which was inherited from the unaffected
mother. Using quantitative PCR, Ravn et al. (2012) mapped the proximal
breakpoint within intron 4 of CUL4B and the distal breakpoint 1,000 bp
downstream of the 3-prime UTR. X-inactivation studies in the unaffected
mother revealed an extremely skewed X-inactivation pattern, consistent
with her being an unaffected carrier.
*FIELD* RF
1. Cabezas, D. A.; Slaugh, R.; Abidi, F.; Arena, J. F.; Stevenson,
R. E.; Schwartz, C. E.; Lubs, H. A.: A new X linked mental retardation
(XLMR) syndrome with short stature, small testes, muscle wasting,
and tremor localises to Xq24-q25. J. Med. Genet. 37: 663-668, 2000.
2. Gong, Y.; Wei, J.; Shao, C.; Guo, Y.; Chen, B.; Guo, C.; Warman,
M.: Mapping of the gene responsible for Smith-Fineman-Myers syndrome
to Xq25. Chinese J. Med. Genet. 16: 277-280, 1999. Note: Article
in Chinese.
3. Isidor, B.; Pichon, O.; Baron, S.; David, A.; Le Caignec, C.:
Deletion of the CUL4B gene in a boy with mental retardation, minor
facial anomalies, short stature, hypogonadism, and ataxia. Am. J.
Med. Genet. 152A: 175-180, 2010.
4. Kerzendorfer, C.; Whibley, A.; Carpenter, G.; Outwin, E.; Chiang,
S.-C.; Turner, G.; Schwartz, C.; El-Khamisy, S.; Raymond, F. L.; O'Driscoll,
M.: Mutations in Cullin 4B result in a human syndrome associated
with increased camptothecin-induced topoisomerase I-dependent DNA
breaks. Hum. Molec. Genet. 19: 1324-1334, 2010.
5. Liu, Q.; Gong, Y.; Chen, B.; Guo, C.; Li, J.; Guo, Y.: [Linkage
analysis of X-linked nuclear protein gene in Smith-Fineman-Myers syndrome.] Chinese
J. Med. Genet. 19: 22-25, 2002. Note: Article in Chinese.
6. Liu, Q. J.; Gong, Y. Q.; Li, J. X.; Zhang, X. Y.; Gao, G. M.; Guo,
Y. S.: [Fine mapping of Smith-Fineman-Myers syndrome and exclusion
of GPC3, GPCR2, MST4 and GLUD2 as candidate genes.] Chinese J. Med.
Genet. 21: 198-202, 2004. Note: Article in Chinese.
7. Ravn, K.; Lindquist, S. G.; Nielsen, K.; Dahm, T. L.; Tumer, Z.
: Deletion of CUL4B leads to concordant phenotype in a monozygotic
twin pair. (Letter) Clin. Genet. 82: 292-294, 2012.
8. Tarpey, P. S.; Raymond, F. L.; O'Meara, S.; Edkins, S.; Teague,
J.; Butler, A.; Dicks, E.; Stevens, C.; Tofts, C.; Avis, T.; Barthorpe,
S.; Buck, G.: and 41 others: Mutations in CUL4B, which encodes
a ubiquitin E3 ligase subunit, cause an X-linked mental retardation
syndrome associated with aggressive outbursts, seizures, relative
macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am.
J. Hum. Genet. 80: 345-352, 2007.
9. Tarpey, P. S.; Smith, R.; Pleasance, E.; Whibley, A.; Edkins, S.;
Hardy, C.; O'Meara, S.; Latimer, C.; Dicks, E.; Menzies, A.; Stephens,
P.; Blow, M.; and 67 others: A systematic, large-scale resequencing
screen of X-chromosome coding exons in mental retardation. Nature
Genet. 41: 535-543, 2009.
10. Wei, J.; Chen, B.; Jiang, Y.; Yang, Y.; Guo, Y.: Smith-Fineman-Myers
syndrome: report on a large family. Am. J. Med. Genet. 47: 307-311,
1993.
11. Zou, Y.; Liu, Q.; Chen, B.; Zhang, X.; Guo, C.; Zhou, H.; Li,
J.; Gao, G.; Guo, Y.; Yan, C.; Wei, J.; Shao, C.; Gong, Y.: Mutation
in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex,
causes X-linked mental retardation. Am. J. Hum. Genet. 80: 561-566,
2007.
*FIELD* CS
INHERITANCE:
X-linked recessive
GROWTH:
[Height];
Short stature (5th percentile);
[Weight];
Central obesity;
Birthweight (<10th percentile)
HEAD AND NECK:
[Head];
Macrocephaly, relative;
[Mouth];
Prominent lower lip;
Macroglossia
CHEST:
[Breasts];
Gynecomastia
GENITOURINARY:
[External genitalia, male];
Hypospadias;
Small penis;
[Internal genitalia, male];
Cryptorchidism;
Small testes
SKELETAL:
Joint laxity;
[Spine];
Kyphosis;
[Hands];
Brachydactyly (in 1 family);
[Feet];
Small feet;
Pes cavus;
Pes planus;
Wide sandal gap
SKIN, NAILS, HAIR:
[Skin];
Striae
MUSCLE, SOFT TISSUE:
Wasted lower leg muscles
NEUROLOGIC:
[Central nervous system];
Mental retardation;
Speech delay, severe;
Lack of speech development;
Tremor;
Decreased fine motor coordination;
Seizures (onset <2 years);
Abnormal gait;
Ataxic gait;
[Behavioral/psychiatric manifestations];
Aggressive outbursts;
Hyperactivity;
Mood swings;
Decreased attention span
VOICE:
Impaired/absent speech
ENDOCRINE FEATURES:
Delayed puberty;
Hypogonadism
MOLECULAR BASIS:
Caused by mutation in the cullin 4B gene (CUL4B, 300304.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/5/2011
*FIELD* CD
Kelly A. Przylepa: 3/6/2008
*FIELD* ED
joanna: 07/02/2013
joanna: 7/17/2012
ckniffin: 1/5/2011
joanna: 3/6/2008
alopez: 8/15/2001
*FIELD* CN
Jill A. Fahrner - updated: 4/5/2013
George E. Tiller - updated: 11/14/2011
Cassandra L. Kniffin - updated: 1/5/2011
Victor A. McKusick - updated: 1/18/2007
*FIELD* CD
Michael J. Wright: 8/15/2001
*FIELD* ED
carol: 09/09/2013
carol: 4/5/2013
carol: 11/17/2011
terry: 11/14/2011
carol: 10/26/2011
wwang: 1/24/2011
ckniffin: 1/5/2011
carol: 11/30/2010
alopez: 10/6/2009
alopez: 1/19/2007
terry: 1/18/2007
ckniffin: 7/20/2005
alopez: 8/15/2001