RBCC Red Blood Cell Collection

KMT2D (ALR, MLL2, MLL4) [Confidence: low (only semi-automatic identification from reviews)]
Histone-lysine N-methyltransferase 2D; Lysine N-methyltransferase 2D; 2.1.1.43 (ALL1-related protein; Myeloid/lymphoid or mixed-lineage leukemia protein 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt O14686
ID KMT2D_HUMAN Reviewed; 5537 AA.
AC O14686; O14687;
DT 10-OCT-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 2.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Histone-lysine N-methyltransferase 2D;
DE Short=Lysine N-methyltransferase 2D;
DE EC=2.1.1.43;
DE AltName: Full=ALL1-related protein;
DE AltName: Full=Myeloid/lymphoid or mixed-lineage leukemia protein 2;
GN Name=KMT2D; Synonyms=ALR, MLL2, MLL4;
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] (ISOFORMS 1 AND 3).
RX PubMed=9247308; DOI=10.1038/sj.onc.1201211;
RA Prasad R., Zhadanov A.B., Sedkov Y., Bullrich F., Druck T.,
RA Rallapalli R., Yano T., Alder H., Croce C.M., Huebner K., Mazo A.,
RA Canaani E.;
RT "Structure and expression pattern of human ALR, a novel gene with
RT strong homology to ALL-1 involved in acute leukemia and to Drosophila
RT trithorax.";
RL Oncogene 15:549-560(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [3]
RP IDENTIFICATION IN THE MLL2/3 COMPLEX.
RC TISSUE=Cervix carcinoma;
RX PubMed=12482968; DOI=10.1128/MCB.23.1.140-149.2003;
RA Goo Y.-H., Sohn Y.C., Kim D.-H., Kim S.-W., Kang M.-J., Jung D.-J.,
RA Kwak E., Barlev N.A., Berger S.L., Chow V.T., Roeder R.G.,
RA Azorsa D.O., Meltzer P.S., Suh P.-G., Song E.J., Lee K.-J., Lee Y.C.,
RA Lee J.W.;
RT "Activating signal cointegrator 2 belongs to a novel steady-state
RT complex that contains a subset of trithorax group proteins.";
RL Mol. Cell. Biol. 23:140-149(2003).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3130, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [5]
RP FUNCTION, ENZYME ACTIVITY, IDENTIFICATION IN THE MLL2 COMPLEX, LXXLL
RP MOTIFS, AND INTERACTION WITH ESR1.
RX PubMed=16603732; DOI=10.1074/jbc.M513245200;
RA Mo R., Rao S.M., Zhu Y.-J.;
RT "Identification of the MLL2 complex as a coactivator for estrogen
RT receptor alpha.";
RL J. Biol. Chem. 281:15714-15720(2006).
RN [6]
RP IDENTIFICATION IN THE MLL2/3 (ASCOM) COMPLEX.
RX PubMed=17021013; DOI=10.1073/pnas.0607313103;
RA Lee S., Lee D.K., Dou Y., Lee J., Lee B., Kwak E., Kong Y.Y.,
RA Lee S.K., Roeder R.G., Lee J.W.;
RT "Coactivator as a target gene specificity determinant for histone H3
RT lysine 4 methyltransferases.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15392-15397(2006).
RN [7]
RP FUNCTION, ENZYME ACTIVITY, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP IDENTIFICATION IN THE MLL2/3 COMPLEX.
RX PubMed=17500065; DOI=10.1074/jbc.M701574200;
RA Cho Y.-W., Hong T., Hong S., Guo H., Yu H., Kim D., Guszczynski T.,
RA Dressler G.R., Copeland T.D., Kalkum M., Ge K.;
RT "PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4
RT methyltransferase complex.";
RL J. Biol. Chem. 282:20395-20406(2007).
RN [8]
RP FUNCTION, AND IDENTIFICATION IN THE MLL2/3 COMPLEX.
RX PubMed=17851529; DOI=10.1038/nature06192;
RA Lan F., Bayliss P.E., Rinn J.L., Whetstine J.R., Wang J.K., Chen S.,
RA Iwase S., Alpatov R., Issaeva I., Canaani E., Roberts T.M.,
RA Chang H.Y., Shi Y.;
RT "A histone H3 lysine 27 demethylase regulates animal posterior
RT development.";
RL Nature 449:689-694(2007).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [10]
RP IDENTIFICATION IN THE MLL2/3 COMPLEX.
RX PubMed=17761849; DOI=10.1126/science.1149042;
RA Lee M.G., Villa R., Trojer P., Norman J., Yan K.P., Reinberg D.,
RA Di Croce L., Shiekhattar R.;
RT "Demethylation of H3K27 regulates polycomb recruitment and H2A
RT ubiquitination.";
RL Science 318:447-450(2007).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-4738, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-27; SER-2274; SER-2309;
RP SER-2311; THR-3197 AND SER-4822, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1671; SER-2274;
RP THR-3197; SER-4359 AND SER-4822, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-2246; LYS-3079; LYS-3433;
RP LYS-4465 AND LYS-4776, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1606; THR-3197;
RP SER-3199; SER-4215; SER-4359 AND SER-4738, 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 [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1671; SER-2274 AND
RP SER-4738, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP VARIANTS KABUK1 CYS-5210 AND ASP-5428, AND VARIANTS THR-692; LEU-813;
RP SER-2382; CYS-2460; LEU-2557; VAL-3398; GLY-3419 AND SER-4357.
RX PubMed=21280141; DOI=10.1002/humu.21416;
RA Paulussen A.D., Stegmann A.P., Blok M.J., Tserpelis D.,
RA Posma-Velter C., Detisch Y., Smeets E.E., Wagemans A., Schrander J.J.,
RA van den Boogaard M.J., van der Smagt J., van Haeringen A.,
RA Stolte-Dijkstra I., Kerstjens-Frederikse W.S., Mancini G.M.,
RA Wessels M.W., Hennekam R.C., Vreeburg M., Geraedts J., de Ravel T.,
RA Fryns J.P., Smeets H.J., Devriendt K., Schrander-Stumpel C.T.;
RT "MLL2 mutation spectrum in 45 patients with Kabuki syndrome.";
RL Hum. Mutat. 32:E2018-E2025(2011).
RN [19]
RP VARIANTS KABUK1 PHE-5109; HIS-5179; HIS-5214; LEU-5340 AND MET-5464.
RX PubMed=20711175; DOI=10.1038/ng.646;
RA Ng S.B., Bigham A.W., Buckingham K.J., Hannibal M.C., McMillin M.J.,
RA Gildersleeve H.I., Beck A.E., Tabor H.K., Cooper G.M., Mefford H.C.,
RA Lee C., Turner E.H., Smith J.D., Rieder M.J., Yoshiura K.,
RA Matsumoto N., Ohta T., Niikawa N., Nickerson D.A., Bamshad M.J.,
RA Shendure J.;
RT "Exome sequencing identifies MLL2 mutations as a cause of Kabuki
RT syndrome.";
RL Nat. Genet. 42:790-793(2010).
CC -!- FUNCTION: Histone methyltransferase. Methylates 'Lys-4' of histone
CC H3 (H3K4me). H3K4me represents a specific tag for epigenetic
CC transcriptional activation. Acts as a coactivator for estrogen
CC receptor by being recruited by ESR1, thereby activating
CC transcription.
CC -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + L-lysine-[histone] =
CC S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone].
CC -!- SUBUNIT: Component of the MLL2/3 complex (also named ASCOM
CC complex), at least composed of KMT2D/MLL2 or KMT2C/MLL3, ASH2L,
CC RBBP5, WDR5, NCOA6, DPY30, KDM6A, PAXIP1/PTIP, PAGR1 and alpha-
CC and beta-tubulin. Interacts with ESR1; interaction is direct.
CC -!- INTERACTION:
CC P03372:ESR1; NbExp=3; IntAct=EBI-996065, EBI-78473;
CC Q14686:NCOA6; NbExp=6; IntAct=EBI-996065, EBI-78670;
CC -!- SUBCELLULAR LOCATION: Nucleus (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O14686-1; Sequence=Displayed;
CC Name=3;
CC IsoId=O14686-3; Sequence=VSP_008560;
CC -!- TISSUE SPECIFICITY: Expressed in most adult tissues, including a
CC variety of hematoipoietic cells, with the exception of the liver.
CC -!- DOMAIN: LXXLL motifs 5 and 6 are essential for the association
CC with ESR1 nuclear receptor.
CC -!- DISEASE: Kabuki syndrome 1 (KABUK1) [MIM:147920]: A congenital
CC mental retardation syndrome with additional features, including
CC postnatal dwarfism, a peculiar facies characterized by long
CC palpebral fissures with eversion of the lateral third of the lower
CC eyelids, a broad and depressed nasal tip, large prominent
CC earlobes, a cleft or high-arched palate, scoliosis, short fifth
CC finger, persistence of fingerpads, radiographic abnormalities of
CC the vertebrae, hands, and hip joints, and recurrent otitis media
CC in infancy. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: This gene mapped to a chromosomal region involved
CC in duplications and translocations associated with cancer.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding
CC methyltransferase superfamily. Histone-lysine methyltransferase
CC family. TRX/MLL subfamily.
CC -!- SIMILARITY: Contains 1 FYR C-terminal domain.
CC -!- SIMILARITY: Contains 1 FYR N-terminal domain.
CC -!- SIMILARITY: Contains 5 PHD-type zinc fingers.
CC -!- SIMILARITY: Contains 1 post-SET domain.
CC -!- SIMILARITY: Contains 4 RING-type zinc fingers.
CC -!- SIMILARITY: Contains 1 SET domain.
CC -!- CAUTION: Another protein KMT2B/MLL4, located on chromosome 19, was
CC first named MLL2 (see AC Q9UMN6). Thus, KMT2B/MLL4 is often
CC referred to as MLL2 and vice versa in the literature.
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DR EMBL; AF010403; AAC51734.1; -; mRNA.
DR EMBL; AF010404; AAC51735.1; -; mRNA.
DR EMBL; AC011603; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; T03454; T03454.
DR PIR; T03455; T03455.
DR RefSeq; NP_003473.3; NM_003482.3.
DR RefSeq; XP_005269219.1; XM_005269162.1.
DR UniGene; Hs.731384; -.
DR PDB; 3UVK; X-ray; 1.40 A; B=5337-5347.
DR PDB; 4ERQ; X-ray; 1.91 A; D/E/F=5333-5346.
DR PDBsum; 3UVK; -.
DR PDBsum; 4ERQ; -.
DR ProteinModelPortal; O14686; -.
DR SMR; O14686; 220-323, 2000-2077.
DR DIP; DIP-37875N; -.
DR IntAct; O14686; 16.
DR MINT; MINT-1192941; -.
DR STRING; 9606.ENSP00000301067; -.
DR ChEMBL; CHEMBL2189114; -.
DR PhosphoSite; O14686; -.
DR PaxDb; O14686; -.
DR PRIDE; O14686; -.
DR Ensembl; ENST00000301067; ENSP00000301067; ENSG00000167548.
DR GeneID; 8085; -.
DR KEGG; hsa:8085; -.
DR UCSC; uc001rta.4; human.
DR CTD; 8085; -.
DR GeneCards; GC12M049413; -.
DR HGNC; HGNC:7133; KMT2D.
DR HPA; HPA035977; -.
DR MIM; 147920; phenotype.
DR MIM; 602113; gene.
DR neXtProt; NX_O14686; -.
DR Orphanet; 2322; Kabuki syndrome.
DR PharmGKB; PA30846; -.
DR eggNOG; COG2940; -.
DR HOVERGEN; HBG006738; -.
DR InParanoid; O14686; -.
DR KO; K09187; -.
DR OMA; PTQHSYT; -.
DR OrthoDB; EOG7N63KQ; -.
DR ChiTaRS; MLL2; human.
DR GeneWiki; MLL2; -.
DR GenomeRNAi; 8085; -.
DR NextBio; 30706; -.
DR PRO; PR:O14686; -.
DR ArrayExpress; O14686; -.
DR Bgee; O14686; -.
DR CleanEx; HS_MLL2; -.
DR Genevestigator; O14686; -.
DR GO; GO:0035097; C:histone methyltransferase complex; IPI:MGI.
DR GO; GO:0018024; F:histone-lysine N-methyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006342; P:chromatin silencing; ISS:UniProtKB.
DR GO; GO:0051568; P:histone H3-K4 methylation; ISS:UniProtKB.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0001555; P:oocyte growth; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IMP:UniProtKB.
DR GO; GO:0033148; P:positive regulation of intracellular estrogen receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IMP:UniProtKB.
DR GO; GO:0043627; P:response to estrogen stimulus; IDA:UniProtKB.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 3.30.40.10; -; 5.
DR InterPro; IPR003889; FYrich_C.
DR InterPro; IPR003888; FYrich_N.
DR InterPro; IPR009071; HMG_box_dom.
DR InterPro; IPR003616; Post-SET_dom.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR001965; Znf_PHD.
DR InterPro; IPR019787; Znf_PHD-finger.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR Pfam; PF05965; FYRC; 1.
DR Pfam; PF05964; FYRN; 1.
DR Pfam; PF00628; PHD; 3.
DR Pfam; PF00856; SET; 1.
DR SMART; SM00542; FYRC; 1.
DR SMART; SM00541; FYRN; 1.
DR SMART; SM00398; HMG; 1.
DR SMART; SM00249; PHD; 7.
DR SMART; SM00508; PostSET; 1.
DR SMART; SM00184; RING; 6.
DR SMART; SM00317; SET; 1.
DR SUPFAM; SSF47095; SSF47095; 1.
DR SUPFAM; SSF57903; SSF57903; 5.
DR PROSITE; PS51543; FYRC; 1.
DR PROSITE; PS51542; FYRN; 1.
DR PROSITE; PS50868; POST_SET; 1.
DR PROSITE; PS50280; SET; 1.
DR PROSITE; PS01359; ZF_PHD_1; 5.
DR PROSITE; PS50016; ZF_PHD_2; 5.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Chromatin regulator;
KW Coiled coil; Complete proteome; Disease mutation; Mental retardation;
KW Metal-binding; Methyltransferase; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat; S-adenosyl-L-methionine;
KW Transcription; Transcription regulation; Transferase; Zinc;
KW Zinc-finger.
FT CHAIN 1 5537 Histone-lysine N-methyltransferase 2D.
FT /FTId=PRO_0000124878.
FT REPEAT 442 446 1.
FT REPEAT 460 464 2.
FT REPEAT 469 473 3.
FT REPEAT 496 500 4.
FT REPEAT 504 508 5.
FT REPEAT 521 525 6.
FT REPEAT 555 559 7.
FT REPEAT 564 568 8.
FT REPEAT 573 577 9.
FT REPEAT 582 586 10.
FT REPEAT 609 613 11.
FT REPEAT 618 622 12.
FT REPEAT 627 631 13.
FT REPEAT 645 649 14.
FT REPEAT 663 667 15.
FT DOMAIN 5175 5235 FYR N-terminal.
FT DOMAIN 5236 5321 FYR C-terminal.
FT DOMAIN 5397 5513 SET.
FT DOMAIN 5521 5537 Post-SET.
FT ZN_FING 226 276 PHD-type 1.
FT ZN_FING 229 274 RING-type 1; atypical.
FT ZN_FING 273 323 PHD-type 2.
FT ZN_FING 276 321 RING-type 2; degenerate.
FT ZN_FING 1377 1430 PHD-type 3.
FT ZN_FING 1427 1477 PHD-type 4.
FT ZN_FING 1504 1559 PHD-type 5.
FT ZN_FING 1507 1557 RING-type 3; atypical.
FT ZN_FING 5092 5137 RING-type 4; degenerate.
FT REGION 439 668 15 X 5 AA repeats of S/P-P-P-E/P-E/A.
FT REGION 5474 5475 S-adenosyl-L-methionine binding (By
FT similarity).
FT COILED 2669 2707 Potential.
FT COILED 3249 3282 Potential.
FT COILED 3562 3614 Potential.
FT COILED 3714 3750 Potential.
FT COILED 3897 3975 Potential.
FT MOTIF 2686 2690 LXXLL motif 1.
FT MOTIF 3038 3042 LXXLL motif 2.
FT MOTIF 4222 4236 LXXLL motif 3.
FT MOTIF 4253 4257 LXXLL motif 4.
FT MOTIF 4463 4467 LXXLL motif 5.
FT MOTIF 4990 4994 LXXLL motif 6.
FT COMPBIAS 229 326 Cys-rich.
FT COMPBIAS 374 1197 Pro-rich.
FT COMPBIAS 1290 1328 Arg-rich.
FT COMPBIAS 1351 1355 Poly-Glu.
FT COMPBIAS 1397 1510 Cys-rich.
FT COMPBIAS 2107 2626 Pro-rich.
FT COMPBIAS 2385 2392 Poly-Pro.
FT COMPBIAS 2707 2713 Poly-Ala.
FT COMPBIAS 2811 2822 Gln-rich.
FT COMPBIAS 2862 2978 Pro-rich.
FT COMPBIAS 3261 4275 Gln-rich.
FT COMPBIAS 4241 4360 Pro-rich.
FT COMPBIAS 4909 4977 Pro-rich.
FT COMPBIAS 5494 5497 Poly-Ile.
FT METAL 5477 5477 Zinc (By similarity).
FT METAL 5525 5525 Zinc (By similarity).
FT METAL 5527 5527 Zinc (By similarity).
FT METAL 5532 5532 Zinc (By similarity).
FT BINDING 5451 5451 S-adenosyl-L-methionine (By similarity).
FT MOD_RES 27 27 Phosphoserine.
FT MOD_RES 1606 1606 Phosphoserine.
FT MOD_RES 1671 1671 Phosphoserine.
FT MOD_RES 2246 2246 N6-acetyllysine.
FT MOD_RES 2274 2274 Phosphoserine.
FT MOD_RES 2309 2309 Phosphoserine.
FT MOD_RES 2311 2311 Phosphoserine.
FT MOD_RES 3079 3079 N6-acetyllysine.
FT MOD_RES 3130 3130 Phosphoserine.
FT MOD_RES 3197 3197 Phosphothreonine.
FT MOD_RES 3199 3199 Phosphoserine.
FT MOD_RES 3433 3433 N6-acetyllysine.
FT MOD_RES 4215 4215 Phosphoserine.
FT MOD_RES 4359 4359 Phosphoserine.
FT MOD_RES 4465 4465 N6-acetyllysine.
FT MOD_RES 4738 4738 Phosphoserine.
FT MOD_RES 4776 4776 N6-acetyllysine.
FT MOD_RES 4822 4822 Phosphoserine.
FT VAR_SEQ 1729 1729 E -> EGET (in isoform 3).
FT /FTId=VSP_008560.
FT VARIANT 476 476 A -> T (in dbSNP:rs1064210).
FT /FTId=VAR_057359.
FT VARIANT 692 692 P -> T (in dbSNP:rs202076833).
FT /FTId=VAR_064370.
FT VARIANT 813 813 P -> L (in dbSNP:rs75226229).
FT /FTId=VAR_064371.
FT VARIANT 2382 2382 P -> S (in dbSNP:rs3741626).
FT /FTId=VAR_064372.
FT VARIANT 2460 2460 R -> C.
FT /FTId=VAR_064373.
FT VARIANT 2557 2557 P -> L (in dbSNP:rs189888707).
FT /FTId=VAR_064374.
FT VARIANT 3398 3398 M -> V (in dbSNP:rs75937132).
FT /FTId=VAR_064375.
FT VARIANT 3419 3419 D -> G (in dbSNP:rs146044282).
FT /FTId=VAR_064376.
FT VARIANT 4357 4357 R -> S.
FT /FTId=VAR_064377.
FT VARIANT 5109 5109 C -> F (in KABUK1).
FT /FTId=VAR_063830.
FT VARIANT 5179 5179 R -> H (in KABUK1).
FT /FTId=VAR_063831.
FT VARIANT 5210 5210 Y -> C (in KABUK1).
FT /FTId=VAR_064378.
FT VARIANT 5214 5214 R -> H (in KABUK1).
FT /FTId=VAR_063832.
FT VARIANT 5224 5224 R -> H (in dbSNP:rs3782356).
FT /FTId=VAR_017115.
FT VARIANT 5340 5340 R -> L (in KABUK1).
FT /FTId=VAR_063833.
FT VARIANT 5428 5428 G -> D (in KABUK1).
FT /FTId=VAR_064379.
FT VARIANT 5464 5464 T -> M (in KABUK1).
FT /FTId=VAR_063834.
FT CONFLICT 5 5 K -> N (in Ref. 1; AAC51734).
FT CONFLICT 14 14 E -> Q (in Ref. 1; AAC51734).
FT CONFLICT 75 75 S -> A (in Ref. 1; AAC51734).
FT CONFLICT 156 156 E -> Q (in Ref. 1; AAC51734).
FT CONFLICT 674 948 Missing (in Ref. 1; AAC51734).
FT CONFLICT 1178 1178 Q -> R (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 1544 1547 EQAA -> DHAP (in Ref. 1; AAC51734/
FT AAC51735).
FT CONFLICT 1761 1761 K -> R (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 1766 1766 D -> G (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 2171 2171 V -> A (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 2413 2413 A -> V (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 3079 3079 K -> E (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 3287 3287 S -> P (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 3319 3319 G -> V (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 3422 3422 D -> G (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4478 4478 R -> Q (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4747 4747 A -> D (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4793 4793 A -> D (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4826 4826 A -> G (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4865 4865 P -> A (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4871 4871 S -> R (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4893 4893 S -> R (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 4974 4974 S -> T (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 5116 5116 A -> G (in Ref. 1; AAC51734/AAC51735).
FT CONFLICT 5522 5522 K -> E (in Ref. 1; AAC51734/AAC51735).
FT HELIX 5339 5341
SQ SEQUENCE 5537 AA; 593389 MW; 31C6DAB0A754F72A CRC64;
MDSQKLAGED KDSEPAADGP AASEDPSATE SDLPNPHVGE VSVLSSGSPR LQETPQDCSG
GPVRRCALCN CGEPSLHGQR ELRRFELPFD WPRCPVVSPG GSPGPNEAVL PSEDLSQIGF
PEGLTPAHLG EPGGSCWAHH WCAAWSAGVW GQEGPELCGV DKAIFSGISQ RCSHCTRLGA
SIPCRSPGCP RLYHFPCATA SGSFLSMKTL QLLCPEHSEG AAYLEEARCA VCEGPGELCD
LFFCTSCGHH YHGACLDTAL TARKRAGWQC PECKVCQACR KPGNDSKMLV CETCDKGYHT
FCLKPPMEEL PAHSWKCKAC RVCRACGAGS AELNPNSEWF ENYSLCHRCH KAQGGQTIRS
VAEQHTPVCS RFSPPEPGDT PTDEPDALYV ACQGQPKGGH VTSMQPKEPG PLQCEAKPLG
KAGVQLEPQL EAPLNEEMPL LPPPEESPLS PPPEESPTSP PPEASRLSPP PEELPASPLP
EALHLSRPLE ESPLSPPPEE SPLSPPPESS PFSPLEESPL SPPEESPPSP ALETPLSPPP
EASPLSPPFE ESPLSPPPEE LPTSPPPEAS RLSPPPEESP MSPPPEESPM SPPPEASRLF
PPFEESPLSP PPEESPLSPP PEASRLSPPP EDSPMSPPPE ESPMSPPPEV SRLSPLPVVS
RLSPPPEESP LSPPPEESPT SPPPEASRLS PPPEDSPTSP PPEDSPASPP PEDSLMSLPL
EESPLLPLPE EPQLCPRSEG PHLSPRPEEP HLSPRPEEPH LSPQAEEPHL SPQPEEPCLC
AVPEEPHLSP QAEGPHLSPQ PEELHLSPQT EEPHLSPVPE EPCLSPQPEE SHLSPQSEEP
CLSPRPEESH LSPELEKPPL SPRPEKPPEE PGQCPAPEEL PLFPPPGEPS LSPLLGEPAL
SEPGEPPLSP LPEELPLSPS GEPSLSPQLM PPDPLPPPLS PIITAAAPPA LSPLGELEYP
FGAKGDSDPE SPLAAPILET PISPPPEANC TDPEPVPPMI LPPSPGSPVG PASPILMEPL
PPQCSPLLQH SLVPQNSPPS QCSPPALPLS VPSPLSPIGK VVGVSDEAEL HEMETEKVSE
PECPALEPSA TSPLPSPMGD LSCPAPSPAP ALDDFSGLGE DTAPLDGIDA PGSQPEPGQT
PGSLASELKG SPVLLDPEEL APVTPMEVYP ECKQTAGQGS PCEEQEEPRA PVAPTPPTLI
KSDIVNEISN LSQGDASASF PGSEPLLGSP DPEGGGSLSM ELGVSTDVSP ARDEGSLRLC
TDSLPETDDS LLCDAGTAIS GGKAEGEKGR RRSSPARSRI KQGRSSSFPG RRRPRGGAHG
GRGRGRARLK STASSIETLV VADIDSSPSK EEEEEDDDTM QNTVVLFSNT DKFVLMQDMC
VVCGSFGRGA EGHLLACSQC SQCYHPYCVN SKITKVMLLK GWRCVECIVC EVCGQASDPS
RLLLCDDCDI SYHTYCLDPP LLTVPKGGWK CKWCVSCMQC GAASPGFHCE WQNSYTHCGP
CASLVTCPIC HAPYVEEDLL IQCRHCERWM HAGCESLFTE DDVEQAADEG FDCVSCQPYV
VKPVAPVAPP ELVPMKVKEP EPQYFRFEGV WLTETGMALL RNLTMSPLHK RRQRRGRLGL
PGEAGLEGSE PSDALGPDDK KDGDLDTDEL LKGEGGVEHM ECEIKLEGPV SPDVEPGKEE
TEESKKRKRK PYRPGIGGFM VRQRKSHTRT KKGPAAQAEV LSGDGQPDEV IPADLPAEGA
VEQSLAEGDE KKKQQRRGRK KSKLEDMFPA YLQEAFFGKE LLDLSRKALF AVGVGRPSFG
LGTPKAKGDG GSERKELPTS QKGDDGPDIA DEESRGLEGK ADTPGPEDGG VKASPVPSDP
EKPGTPGEGM LSSDLDRIST EELPKMESKD LQQLFKDVLG SEREQHLGCG TPGLEGSRTP
LQRPFLQGGL PLGNLPSSSP MDSYPGLCQS PFLDSRERGG FFSPEPGEPD SPWTGSGGTT
PSTPTTPTTE GEGDGLSYNQ RSLQRWEKDE ELGQLSTISP VLYANINFPN LKQDYPDWSS
RCKQIMKLWR KVPAADKAPY LQKAKDNRAA HRINKVQKQA ESQINKQTKV GDIARKTDRP
ALHLRIPPQP GALGSPPPAA APTIFIGSPT TPAGLSTSAD GFLKPPAGSV PGPDSPGELF
LKLPPQVPAQ VPSQDPFGLA PAYPLEPRFP TAPPTYPPYP SPTGAPAQPP MLGASSRPGA
GQPGEFHTTP PGTPRHQPST PDPFLKPRCP SLDNLAVPES PGVGGGKASE PLLSPPPFGE
SRKALEVKKE ELGASSPSYG PPNLGFVDSP SSGTHLGGLE LKTPDVFKAP LTPRASQVEP
QSPGLGLRPQ EPPPAQALAP SPPSHPDIFR PGSYTDPYAQ PPLTPRPQPP PPESCCALPP
RSLPSDPFSR VPASPQSQSS SQSPLTPRPL SAEAFCPSPV TPRFQSPDPY SRPPSRPQSR
DPFAPLHKPP RPQPPEVAFK AGSLAHTSLG AGGFPAALPA GPAGELHAKV PSGQPPNFVR
SPGTGAFVGT PSPMRFTFPQ AVGEPSLKPP VPQPGLPPPH GINSHFGPGP TLGKPQSTNY
TVATGNFHPS GSPLGPSSGS TGESYGLSPL RPPSVLPPPA PDGSLPYLSH GASQRSGITS
PVEKREDPGT GMGSSLATAE LPGTQDPGMS GLSQTELEKQ RQRQRLRELL IRQQIQRNTL
RQEKETAAAA AGAVGPPGSW GAEPSSPAFE QLSRGQTPFA GTQDKSSLVG LPPSKLSGPI
LGPGSFPSDD RLSRPPPPAT PSSMDVNSRQ LVGGSQAFYQ RAPYPGSLPL QQQQQQLWQQ
QQATAATSMR FAMSARFPST PGPELGRQAL GSPLAGISTR LPGPGEPVPG PAGPAQFIEL
RHNVQKGLGP GGTPFPGQGP PQRPRFYPVS EDPHRLAPEG LRGLAVSGLP PQKPSAPPAP
ELNNSLHPTP HTKGPTLPTG LELVNRPPSS TELGRPNPLA LEAGKLPCED PELDDDFDAH
KALEDDEELA HLGLGVDVAK GDDELGTLEN LETNDPHLDD LLNGDEFDLL AYTDPELDTG
DKKDIFNEHL RLVESANEKA EREALLRGVE PGPLGPEERP PPAADASEPR LASVLPEVKP
KVEEGGRHPS PCQFTIATPK VEPAPAANSL GLGLKPGQSM MGSRDTRMGT GPFSSSGHTA
EKASFGATGG PPAHLLTPSP LSGPGGSSLL EKFELESGAL TLPGGPAASG DELDKMESSL
VASELPLLIE DLLEHEKKEL QKKQQLSAQL QPAQQQQQQQ QQHSLLSAPG PAQAMSLPHE
GSSPSLAGSQ QQLSLGLAGA RQPGLPQPLM PTQPPAHALQ QRLAPSMAMV SNQGHMLSGQ
HGGQAGLVPQ QSSQPVLSQK PMGTMPPSMC MKPQQLAMQQ QLANSFFPDT DLDKFAAEDI
IDPIAKAKMV ALKGIKKVMA QGSIGVAPGM NRQQVSLLAQ RLSGGPSSDL QNHVAAGSGQ
ERSAGDPSQP RPNPPTFAQG VINEADQRQY EEWLFHTQQL LQMQLKVLEE QIGVHRKSRK
ALCAKQRTAK KAGREFPEAD AEKLKLVTEQ QSKIQKQLDQ VRKQQKEHTN LMAEYRNKQQ
QQQQQQQQQQ QQHSAVLALS PSQSPRLLTK LPGQLLPGHG LQPPQGPPGG QAGGLRLTPG
GMALPGQPGG PFLNTALAQQ QQQQHSGGAG SLAGPSGGFF PGNLALRSLG PDSRLLQERQ
LQLQQQRMQL AQKLQQQQQQ QQQQQHLLGQ VAIQQQQQQG PGVQTNQALG PKPQGLMPPS
SHQGLLVQQL SPQPPQGPQG MLGPAQVAVL QQQHPGALGP QGPHRQVLMT QSRVLSSPQL
AQQGQGLMGH RLVTAQQQQQ QQQHQQQGSM AGLSHLQQSL MSHSGQPKLS AQPMGSLQQL
QQQQQLQQQQ QLQQQQQQQL QQQQQLQQQQ LQQQQQQQQL QQQQQQQLQQ QQQQLQQQQQ
QQQQQFQQQQ QQQQMGLLNQ SRTLLSPQQQ QQQQVALGPG MPAKPLQHFS SPGALGPTLL
LTGKEQNTVD PAVSSEATEG PSTHQGGPLA IGTTPESMAT EPGEVKPSLS GDSQLLLVQP
QPQPQPSSLQ LQPPLRLPGQ QQQQVSLLHT AGGGSHGQLG SGSSSEASSV PHLLAQPSVS
LGDQPGSMTQ NLLGPQQPML ERPMQNNTGP QPPKPGPVLQ SGQGLPGVGI MPTVGQLRAQ
LQGVLAKNPQ LRHLSPQQQQ QLQALLMQRQ LQQSQAVRQT PPYQEPGTQT SPLQGLLGCQ
PQLGGFPGPQ TGPLQELGAG PRPQGPPRLP APPGALSTGP VLGPVHPTPP PSSPQEPKRP
SQLPSPSSQL PTEAQLPPTH PGTPKPQGPT LEPPPGRVSP AAAQLADTLF SKGLGPWDPP
DNLAETQKPE QSSLVPGHLD QVNGQVVPEA SQLSIKQEPR EEPCALGAQS VKREANGEPI
GAPGTSNHLL LAGPRSEAGH LLLQKLLRAK NVQLSTGRGS EGLRAEINGH IDSKLAGLEQ
KLQGTPSNKE DAAARKPLTP KPKRVQKASD RLVSSRKKLR KEDGVRASEA LLKQLKQELS
LLPLTEPAIT ANFSLFAPFG SGCPVNGQSQ LRGAFGSGAL PTGPDYYSQL LTKNNLSNPP
TPPSSLPPTP PPSVQQKMVN GVTPSEELGE HPKDAASARD SERALRDTSE VKSLDLLAAL
PTPPHNQTED VRMESDEDSD SPDSIVPASS PESILGEEAP RFPHLGSGRW EQEDRALSPV
IPLIPRASIP VFPDTKPYGA LGLEVPGKLP VTTWEKGKGS EVSVMLTVSA AAAKNLNGVM
VAVAELLSMK IPNSYEVLFP ESPARAGTEP KKGEAEGPGG KEKGLEGKSP DTGPDWLKQF
DAVLPGYTLK SQLDILSLLK QESPAPEPPT QHSYTYNVSN LDVRQLSAPP PEEPSPPPSP
LAPSPASPPT EPLVELPTEP LAEPPVPSPL PLASSPESAR PKPRARPPEE GEDSRPPRLK
KWKGVRWKRL RLLLTIQKGS GRQEDEREVA EFMEQLGTAL RPDKVPRDMR RCCFCHEEGD
GATDGPARLL NLDLDLWVHL NCALWSTEVY ETQGGALMNV EVALHRGLLT KCSLCQRTGA
TSSCNRMRCP NVYHFACAIR AKCMFFKDKT MLCPMHKIKG PCEQELSSFA VFRRVYIERD
EVKQIASIIQ RGERLHMFRV GGLVFHAIGQ LLPHQMADFH SATALYPVGY EATRIYWSLR
TNNRRCCYRC SIGENNGRPE FVIKVIEQGL EDLVFTDASP QAVWNRIIEP VAAMRKEADM
LRLFPEYLKG EELFGLTVHA VLRIAESLPG VESCQNYLFR YGRHPLMELP LMINPTGCAR
SEPKILTHYK RPHTLNSTSM SKAYQSTFTG ETNTPYSKQF VHSKSSQYRR LRTEWKNNVY
LARSRIQGLG LYAAKDLEKH TMVIEYIGTI IRNEVANRRE KIYEEQNRGI YMFRINNEHV
IDATLTGGPA RYINHSCAPN CVAEVVTFDK EDKIIIISSR RIPKGEELTY DYQFDFEDDQ
HKIPCHCGAW NCRKWMN
//

MIM 147920
*RECORD*
*FIELD* NO
147920
*FIELD* TI
#147920 KABUKI SYNDROME 1; KABUK1
;;KABUKI SYNDROME;;
KABUKI MAKE-UP SYNDROME; KMS;;
read moreNIIKAWA-KUROKI SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because Kabuki syndrome-1
(KABUK1) is caused by heterozygous mutation in the MLL2 gene (602113) on
chromosome 12q12-q14.

DESCRIPTION

Kabuki syndrome is a congenital mental retardation syndrome with
additional features, including postnatal dwarfism, a peculiar facies
characterized by long palpebral fissures with eversion of the lateral
third of the lower eyelids (reminiscent of the make-up of actors of
Kabuki, a Japanese traditional theatrical form), a broad and depressed
nasal tip, large prominent earlobes, a cleft or high-arched palate,
scoliosis, short fifth finger, persistence of fingerpads, radiographic
abnormalities of the vertebrae, hands, and hip joints, and recurrent
otitis media in infancy (Niikawa et al., 1981).

- Genetic Heterogeneity

Kabuki syndrome-2 (300867) is caused by mutation in the KDM6A gene
(300128) on chromosome Xp11.3.

CLINICAL FEATURES

Niikawa et al. (1988) collected data from 62 patients with Kabuki
syndrome from 33 institutions, almost all of them in Japan. Most of the
patients had 5 cardinal manifestations: (1) a peculiar face in all
cases, characterized by eversion of the lower lateral eyelid, arched
eyebrows with sparse or dispersed lateral one-third, depressed nasal
tip, and prominent ears; (2) skeletal anomalies in 92%, including
brachydactyly V and spinal deformity with or without sagittal cleft
vertebrae; (3) dermatoglyphic abnormalities in 93%, including increased
digital ulnar loop and hypothenar loop patterns, absence of the digital
triradius c and/or d, and presence of fingertip pads; (4) mild to
moderate mental retardation in 92%; and (5) postnatal growth deficiency
in 83%. Fetal finger pads, which are typical of Kabuki syndrome, occur
also in the FG syndrome (305450). Early breast development occurred in
23% of infant girls. Congenital heart defects, including single
ventricle with a common atrium, ventricular septal defect, atrial septal
defect, tetralogy of Fallot, coarctation of aorta, patent ductus
arteriosus (see 607411), aneurysm of aorta, transposition of great
vessels, and right bundle branch block, were observed in 31% of the
patients. Of the 62 Kabuki syndrome patients, 58 were Japanese. The
incidence of the disorder in Japanese newborns was estimated at 1 in
32,000. All cases were sporadic. The sex ratio was even, and there was
no correlation with birth order. Consanguinity was not increased among
the parents, and no exogenous agent could be incriminated. Three of the
62 patients had a Y chromosome abnormality involving Yp11.2. In general,
the findings of Niikawa et al. (1988) were considered compatible with an
autosomal dominant disorder in which each patient represents a fresh
mutation. A mutation rate was calculated at 15.6 x 10(-6) per gamete per
generation. (The abstract of Niikawa et al. (1988) incorrectly stated
the rate to be 15.6 x 10(6).) The possibility of the location of the
gene in the pseudoautosomal region of the X chromosome was also raised.

Clarke and Hall (1990) described 3 unrelated Caucasian children with
this syndrome. Gillis et al. (1990) described the disorder in a child of
Arab descent. Philip et al. (1992) studied 16 non-Japanese cases from
Europe and North America. They concluded that the facial phenotype is
specific and easily recognizable regardless of ethnic origin. Postnatal
growth retardation and mild mental retardation were confirmed to be
cardinal manifestations. Significant neurologic dysfunction other than
mental retardation and joint hypermobility appeared to be more common in
the non-Japanese patients.

Hughes and Davies (1994) presented 20 unselected cases with a definitive
diagnosis of Kabuki syndrome: 6 boys and 14 girls, ranging in age from
10 months to 13 years. The incidence of heart abnormalities in these
children was almost twice that previously reported (55%) and juxtaductal
coarctation occurred with a frequency of 25%. One of the patients
pictured by Hughes and Davies (1994) showed the accentuated depression
that is often seen below the midpoint of the lower lip.

Ilyina et al. (1995) reported 10 patients of European ancestry from
Byelorussia, Russia, and Moldavia. They emphasized prominent and broad
philtrum as an important component. Some clinical manifestations were
observed in parents and other relatives in 3 generations of 3 families.
Ilyina et al. (1995) favored autosomal dominant inheritance with
variable expressivity.

Burke and Jones (1995) reported 8 cases of Kabuki syndrome in
non-Japanese patients. They commented that the phenotype appears to
evolve over time, making the diagnosis difficult in infancy. They stated
that cleft palate occurs in about 40% of patients. Galan-Gomez et al.
(1995) described Kabuki syndrome in 5 Spanish children, 3 females and 2
males. Sagittal vertebral clefts and dermatoglyphic abnormalities were
present in all 5; general heart defects were present in 4.

Halal et al. (1989) reported an instance of probable autosomal dominant
inheritance of the Kabuki syndrome; a father and his 2 children were
affected. The father had milder symptoms than the offspring, but had
typical facial changes and was of normal intelligence. Kobayashi and
Sakuragawa (1996) described a family in which a 45-year-old business man
and his 17-year-old daughter, born to nonconsanguineous parents, were
affected. The father had characteristic facial abnormalities of Kabuki
syndrome, including long palpebral fissures, long eyelashes, and a
prominent nose. He was of normal stature and there were no deformities
of the fingers, feet, or ribs. However, he had all ulnar loop patterns
on the fingertips, and lacked palmar triradii c and d. His mental status
was above average. In the daughter, a ventricular septal defect had been
surgically closed at age 6 years. Her psychomotor development was
delayed and school performance was poor. She was 146.5 cm tall at the
age of 17. She had epicanthic folds, long palpebral fissures,
high-arched eyebrows sparse in the lateral one-third, a broad and
depressed nasal tip, a short nasal septum, and large malformed ears. Her
fingers were stubby with bilateral clinodactyly of the fifth fingers,
and the first toes were hyperplastic. On fingertips she had an increased
number of ulnar loops, and she lacked palmar triradii c and d. There was
a hypothenar ulnar loop, and fingertip pads were found on all fingers, a
common finding in Kabuki syndrome. Her IQ was estimated to be 60. The
mother was of normal height and had no minor anomalies or abnormal
dermatoglyphic patterns.

Silengo et al. (1996) reported an Italian girl with typical findings of
Kabuki syndrome and a mildly affected mother. The fact that males and
females are equally affected, that the consanguinity rate is not
increased, that parents and other relatives of patients show a facial
resemblance, and that the condition is transmitted vertically with
variable clinical manifestations in familial cases are all compatible
with autosomal dominant inheritance. Sporadic cases may represent new
mutations.

Tsukahara et al. (1997) described 4 individuals with Kabuki syndrome in
2 families. In family 1, the proposita, a 2-year-old girl, and her
mother had typical Kabuki syndrome. The proposita also had early breast
development. In family 2, the proposita, a 6-month-old girl, and her
mother had typical Kabuki syndrome. The proposita died at age 6 months
as a result of complications of a cardiac malformation.

In a girl with Kabuki syndrome, Lerone et al. (1997) described conical
incisors, hypodontia, hypoplastic nails, and brittle hair. Although
abnormal teeth have commonly been described in this disorder, hair
abnormalities have never been investigated.

Dominant inheritance with variable expressivity was supported by the
mother and child reported by Courtens et al. (2000). The 18-month-old
daughter had facial features characteristic of Kabuki syndrome,
prominent fingertips, a midsagittal cleft of vertebral body thoracic-4,
hypotonia, and psychomotor retardation. The mother had a similar facial
appearance, prominent, cup-shaped ears, abnormal dentition, early breast
development, and low normal intelligence. The maternal grandmother had
the same facial appearance and 3 maternal aunts reportedly likewise
showed these features. Microscopic examination of the hair of the
proposita showed abnormalities consisting of trichorrhexis nodosa,
twisting of the hair shafts, and irregularity of the diameter of the
hair, all changes similar to those reported by Lerone et al. (1997).

Shotelersuk et al. (2002) described 6 Thai children with the Kabuki
syndrome, including monozygotic twins who are discordant for the
syndrome. In another family, a mother had a facial appearance similar to
that of her affected son, suggesting autosomal dominant inheritance.
Common findings included lower lip pits with or without symmetrical
lower lip nodules and pilonidal sinuses. Early eruption of the 2 lower
central incisors, transient hyperthyrotropinemia in infancy, and aplasia
cutis were also observed.

Wilson (1998) compared 8 new and 5 previously illustrated cases of this
syndrome with those in the literature, providing data on 183 cases. A
total of 108 non-Asian patients had been reported.

Although hydronephrosis had been reported in a few cases of Kabuki
syndrome, Ewart-Toland et al. (1998) reported the first cases of Kabuki
syndrome with hepatic anomalies. They described 2 patients with renal
and/or hepatic anomalies requiring transplantation. Both patients had
the characteristic facial appearance of children with Kabuki syndrome,
postnatal growth deficiency, and developmental delay. At birth, 1
patient presented with hypoglycemia, ileal perforation, right
hydroureter, and hydronephrosis. The patient subsequently developed
hyperbilirubinemia, hepatic abscess, and cholangitis. At age 8 months,
he underwent a liver transplant. Hepatic pathology was interpreted as
neonatal sclerosing cholangitis. Case 2 presented with renal failure at
age 6 years. Renal ultrasound showed markedly dysplastic kidneys
requiring transplantation. In addition to characteristic findings of
Kabuki syndrome, she had coronal synostosis and was shown to have immune
deficiency and an autoimmune disorder manifesting as Hashimoto
thyroiditis and vitiligo.

Kawame et al. (1999) analyzed the clinical findings of Kabuki syndrome
in 18 North American children. Most had postnatal growth retardation,
and all had developmental delay and hypotonia. Feeding difficulties,
with or without cleft palate, were common; 5 patients required
gastrostomy tube placement. In all but 2 patients, developmental
quotients/IQs were 60 or less. Seizures were seen in less than half of
the patients, but ophthalmologic and otologic problems were common,
particularly recurrent otitis media. Congenital heart defects were
present in 7 (39%); 3 patients underwent repair of coarctation of the
aorta. Other features included urinary tract anomalies, malabsorption,
joint hypermobility and dislocation, congenital hypothyroidism,
idiopathic thrombocytopenic purpura, and, in 1 patient, autoimmune
hemolytic anemia and hypogammaglobulinemia. All patients had negative
family histories for Kabuki syndrome.

McGaughran et al. (2000) described 2 females with typical Kabuki
syndrome who presented in the first year of life with extrahepatic
biliary atresia, a previously undescribed complication of the syndrome.
Selicorni et al. (2001) described a similar case of atresia of the
extrahepatic bile ducts and common bile duct identified in a 44-day-old
infant. A Kasai procedure was performed at that time with complete
disappearance of jaundice by the age of 5 months. However, recurrence of
symptoms required liver transplantation which was successfully performed
at the age of 20 years; she was in good condition 5 years thereafter.

Donadio et al. (2000) reported an Italian girl with Kabuki syndrome and
diaphragmatic hernia. Donadio et al. (2000) reviewed 3 other cases of
Kabuki syndrome with diaphragmatic defects, all of non-Asian origin.

Van Haelst et al. (2000) reported 2 patients with Kabuki syndrome and
stenosis of the central airways (one with local stenosis of the right
upper lobe bronchus, and the other with severe bronchomalacia and an
abnormal right bronchial tree), a complication not previously reported
in patients with Kabuki syndrome. One of the patients also had
extrahepatic biliary atresia, and the other had congenital diaphragmatic
hernia.

Kokitsu-Nakata et al. (1999) reported the case of a Brazilian girl with
Kabuki syndrome associated with lower lip pits and anorectal anomalies.
They found reports of at least 4 patients with Kabuki syndrome and
anorectal anomalies (Matsumura et al., 1992). They found reports of
lower lip pits only in a Kabuki syndrome patient reported by
Franceschini et al., 1993. However, Makita et al. (1999) reported a
5-year-old Japanese girl with clinical manifestations of both Kabuki
syndrome and the van der Woude lip-pit syndrome (VWS; 119300). Assuming
that the association of the 2 syndromes was caused by a microdeletion
involving putative genes for the 2 disorders, Makita et al. (1999)
carried out fluorescence in situ hybridization and microsatellite
analyses using PAC clones and dinucleotide repeat markers spanning the
VWS1 critical region at 1q32-q41. No deletion was detected.

Igawa et al. (2000) studied 3 patients with Kabuki syndrome for middle
and inner ear abnormalities by using CT of the petrous bones. No middle
ear abnormalities were identified, but all 3 patients had bilateral
dysplasia of the inner ear (hypodysplasia of the cochlea, vestibule, and
semicircular canals). Audiometry on 2 of the patients showed a sharp
decrease in hearing of the high tone range, bilateral in one and
unilateral in the other. The authors concluded that CT of the petrous
bones and audiometry should be performed in early infancy on all
patients with Kabuki syndrome.

Matsune et al. (2001) described oral manifestations in 6 patients with
Kabuki syndrome. These included a high-arched palate, malocclusion,
microdontia, a small dental arch, hypodontia, severe maxillary
recession, and midfacial hypoplasia.

McGaughran et al. (2001) described 9 patients with Kabuki syndrome from
New Zealand, all having the characteristic facial dysmorphism and many
of the well-described associated anomalies. Some had unusual
abnormalities, including diaphragmatic eventration, severe congenital
mitral stenosis, idiopathic thrombocytopenic purpura, and vitiligo. They
also reported Arnold Chiari type 1 malformation and epibulbar dermoids,
neither of which had been previously reported in this syndrome.

Digilio et al. (2001) presented the results of cardiac evaluations of 60
patients diagnosed with Kabuki syndrome at their institution. Cardiac
evaluation included chest radiograph, electrocardiogram, and
2-dimensional and color Doppler echocardiography. Thirty-five of the
patients (58%) had congenital heart defects. The most commonly observed
defects were coarctation of the aorta (23%), atrial septal defect (20%),
and ventricular septal defect (17%).

Kurosawa et al. (2002) reported 4 patients with Kabuki syndrome and
patellar dislocation and reviewed 6 previously reported patients with
this combination. In their 4 patients, the age at diagnosis of the
patellar dislocation ranged from 11 to 23 years. Of the patients in whom
gender was known, 7 were female and 2 were male. The authors concluded
that patellar dislocation may be frequent among older children and young
adults with Kabuki syndrome, especially among obese female patients with
lax knee joints.

Fryns and Devriendt (1998) described an 8-year-old girl with signs and
symptoms thought to be consistent with Kabuki syndrome. She also had
bilateral defective, bipartite clavicles. Hinrichs et al. (2002)
described 2 unrelated patients with this type of clavicular defect in
association with Kabuki syndrome.

Mihci et al. (2002) described a 7-year-old boy with Kabuki syndrome
whose head MRI showed migration defects, including periventricular
nodular heterotopia present along the walls of both lateral ventricles
and an underdeveloped corpus callosum.

Ming et al. (2003) reported 3 children with Kabuki syndrome who also had
retinal coloboma. A diagnosis of CHARGE association (214800) was
initially suggested in 2 of the patients before the typical facial
features of Kabuki syndrome emerged. A review of reported cases showed
that the incidence of coloboma is greatly increased in Kabuki syndrome.

White et al. (2004) documented the phenotype of 27 children and adults
with Kabuki syndrome from Australia and New Zealand. Parents reported a
behavior phenotype characterized by the avoidance of eye contact, a love
of music, and an excellent long-term memory. There was no correlation
between head circumference and severity of intellectual disability. Six
of their patients showed a characteristic growth profile, with failure
to thrive in infancy progressing to obesity or overweight in middle
childhood or adolescence.

Wessels et al. (2002) reviewed the characteristics of Kabuki syndrome in
300 patients. Typical findings included mild to moderate mental
retardation, fetal pads, cleft palate, and characteristic facies with
long palpebral fissures, everted lower lateral eyelids, and arched
eyebrows. Postnatal growth retardation and skeletal and visceral
anomalies were present in a large percentage of the patients.

Genevieve et al. (2004) described 8 patients from a series of 20 who had
atypical findings in Kabuki syndrome. Rare or atypical features included
the following: chronic and/or severe diarrhea (4/20) including celiac
disease, diaphragmatic defects (3/20), pseudarthrosis of the clavicles
(2/20), vitiligo (2/20), and persistent hypoglycemia (2/20). Other
occasional findings were severe autoimmune thrombopenia, cerebellar
vermis atrophy, and myopathic features. One patient presented with a
clinical overlap with CHARGE syndrome (214800).

Adam and Hudgins (2004) provided a detailed review of the clinical
features, diagnostic criteria, and cytogenic abnormalities reported in
Kabuki syndrome.

Turner et al. (2005) reported 7 patients with Kabuki syndrome. Three
patients had previously undetected ocular abnormalities, including
myopia, ptosis, strabismus, and tilted discs. Four patients had
nocturnal lagophthalmos (sleeping with the eyes open). There was no
evidence of an 8p duplication in any of the patients.

Hoffman et al. (2005) performed immunologic evaluation of 19 consecutive
individuals with Kabuki syndrome and found decreased IgA levels in 15 of
19 patients (79%), 2 of whom had undetectable levels. Eight patients
(42%) also had low total IgG levels, and specific IgG subclass
abnormalities were found in 6 of 13 patients evaluated; IgM levels were
less frequently decreased. One patient failed to generate anti-tetanus
antibodies despite immunization. Hoffman et al. (2005) suggested that
hypogammaglobulinemia is a frequent finding in Kabuki syndrome and noted
that the pattern of antibody abnormalities resembles common variable
immune deficiency (CVID; 240500).

POPULATION GENETICS

Kabuki syndrome is estimated to occur in at least 1 per 32,000 Japanese
individuals (Niikawa et al., 1988).

CYTOGENETICS

Li et al. (1996) excluded microdeletion within 22q11.2 as a causative
factor of the syndrome in 5 patients (3 Japanese children, a German
girl, and a Colombian boy). The region was chosen for study because of
the presence of congenital heart defects in patients with Kabuki
syndrome and speculation that the condition might have a common
molecular cause with the 22q11.2 deletion syndromes, DiGeorge syndrome
(188400) and velocardiofacial syndrome (192430).

Lo et al. (1998) found an interstitial duplication of the short arm of
chromosome 1 with breakpoints involving 1p13.1 and 1p22.1 in a patient
with some features suggesting Kabuki syndrome, i.e., mental retardation,
small head, eversion of the lateral part of the lower eyelids,
epicanthic folds, lateral flare of the eyebrows, short columella, and
persistent fetal finger pads. Other chromosome abnormalities described
in this disorder, usually as isolated cases, were reviewed.

Using comparative genomic hybridization (CGH), Milunsky and Huang (2003)
found an 8p23.1-p22 duplication in 6 unrelated patients with Kabuki
syndrome. They delimited the duplicated region in all cases to
approximately 3.5 Mb by BAC-FISH analysis. No duplication of this region
was found in 2 parents or 20 controls by either CGH or BAC-FISH. Because
the 6 patients with Kabuki syndrome represented different races, the
authors suggested that the duplication may represent a common etiologic
basis for the disorder.

By FISH using 15 BAC clones covering 8p23.1-p22, Miyake et al. (2004)
did not detect any duplication in 26 Japanese and 2 Thai patients with
Kabuki syndrome. Based on examination of the facial photographs of cases
1 and 2 in the report by Milunsky and Huang (2003), Miyake et al. (2004)
suggested that the patient populations studied may differ clinically,
with the earlier reported patients having an 'atypical Kabuki syndrome.'

Using array-based comparative genomic hybridization and FISH, Hoffman et
al. (2005) failed to detect a duplication of 8p23.1-p22 in 15 patients
with Kabuki syndrome and suggested that the 8p duplication may not be a
common mechanism for Kabuki syndrome.

MOLECULAR GENETICS

Ng et al. (2010) performed the exome sequencing of 10 unrelated patients
with Kabuki syndrome, 7 of European ancestry, 2 of Hispanic ancestry and
1 of mixed European and Haitian ancestry, and identified nonsense or
frameshift mutations in the MLL2 gene in 7 patients. Follow-up Sanger
sequencing detected MLL2 mutations in 2 of the 3 remaining individuals
with Kabuki syndrome and in 26 of 43 additional cases. In all, they
identified 33 distinct MLL2 mutations in 35 of 53 families (66%) with
Kabuki syndrome (see, e.g., 602113.0001-602113.0004). In each of 12
cases for which DNA from both parents was available, the MLL2 variant
was found to have occurred de novo. MLL2 mutations were also identified
in each of 2 families in which Kabuki syndrome was transmitted from
parent to child. None of the additional MLL2 mutations was found in 190
control chromosomes from individuals of matched geographic ancestry. Ng
et al. (2010) suggested that mutations in MLL2 are a major cause of
Kabuki syndrome.

Hannibal et al. (2011) identified 70 mutations in the MLL2 gene in 81
(74%) of 110 kindreds with Kabuki syndrome. In simplex cases for which
DNA was available from both parents, 25 mutations were confirmed to be
de novo, whereas a transmitted mutation was found in 2 of 3 familial
cases. Most of the variants were nonsense or frameshift mutations
predicted to result in haploinsufficiency. Mutations occurred throughout
the gene, but were particularly common in exons 39 and 48. The clinical
features of those with or without mutations were similar, except for
renal anomalies, which occurred in 47% of mutation carriers compared to
14% of those who did not have a mutation.

Li et al. (2011) sequenced all 54 coding exons of the MLL2 gene in 34
patients with Kabuki syndrome and identified 18 distinct mutations in 19
patients, 11 of 12 tested de novo. Mutations were located throughout the
gene and included 3 nonsense mutations, 2 splice site mutations, 6 small
deletions or insertions, and 7 missense mutations. Li et al. (2011)
compared frequencies of clinical symptoms in MLL2 mutation carriers
versus noncarriers. MLL2 mutation carriers more often presented with
short stature and renal anomalies (p = 0.026 and 0.031, respectively),
and in addition, MLL2 showed a more typical facial gestalt (17 of 19)
compared with noncarriers (9 of 15), although this result was not
statistically significant (p = 0.1).

Miyake et al. (2013) identified MLL2 mutations in 50 (61.7%) of 81
patients with Kabuki syndrome. Most (70%) of the MLL2 mutations were
predicted to be protein-truncating. The truncating mutations were
distributed throughout the coding region, whereas the nontruncating
mutations were most often within or adjacent to functional domains.

- Genotype-Phenotype Correlations

Banka et al. (2012) analyzed the MLL2 gene in a cohort of 116 patients
with Kabuki syndrome, including 18 patients previously reported by
Hannibal et al. (2011), and identified MLL2 variants in 74 (63.8%).
Systematic Kabuki syndrome facial morphology study suggested that nearly
all patients with typical Kabuki syndrome facial features have
pathogenic MLL2 mutations, although the disorder can be phenotypically
variable. In addition, Banka et al. (2012) showed that KABUK1 patients
were more likely to have feeding problems, kidney anomalies, early
breast bud development, joint dislocations, and palatal malformations in
comparison with MLL2 mutation-negative patients. Banka et al. (2012)
concluded that the genetic heterogeneity of Kabuki syndrome is not as
extensive as previously suggested; however, given the phenotypic
variability of the disorder, MLL2 testing should be considered even in
atypical patients.

Miyake et al. (2013) screened 81 patients with Kabuki syndrome for
mutations in the MLL2 and KDM6A genes and identified MLL2 mutations in
50 (61.7%) and KDM6A mutations in 5 (6.2%). Patients with MLL2
truncating mutations (70%) had facies that were more typical of those
seen in the patients originally reported with Kabuki syndrome.
High-arched eyebrows, short fifth fingers, and infantile hypotonia were
more commonly seen in patients with MLL2 mutations than in those with
KDM6A mutations. Only half of the patients with MLL2 mutations had short
stature and postnatal growth retardation, compared to all of the
patients with KDM6A mutations.

- Exclusion Studies

Bottani et al. (2006) screened the TGFBR1 (190181) and TGFBR1 (190182)
genes in 14 typical Kabuki patients and found no mutations.

In a girl with Kabuki syndrome, Maas et al. (2007) identified a
heterozygous de novo 250-kb deletion in the MACROD2 gene (611567) at
chromosome 20p12.1. No deletions or pathogenic mutations in the MACROD2
or FLRT3 (604808) genes were identified in 19 additional patients with
Kabuki syndrome.

Among 43 Japanese patients with Kabuki syndrome, Kuniba et al. (2008)
did not find mutations or deletions in the MACROD2 or FLRT3 genes.

Of 34 patients with Kabuki syndrome, Li et al. (2011) failed to find
mutations in the MLL2 gene in 15. Mutation-negative patients were
subsequently tested for mutations in 10 functional candidate genes, but
no convincing causative mutations could be identified. Li et al. (2011)
concluded that MLL2 is the major gene for Kabuki syndrome with a wide
spectrum of de novo mutations but that there is further genetic
heterogeneity accounting for MLL2 mutation-negative patients.

NOMENCLATURE

Several authors, including Hughes and Davies (1994) and Burke and Jones
(1995), have recommended that the term 'make-up' be removed from the
designation of this syndrome because some families consider the term
objectionable.

*FIELD* SA
Kuroki et al. (1981); Niikawa et al. (1982)
*FIELD* RF
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47. Niikawa, N.; Matsuura, N.; Fukushima, Y.; Ohsawa, T.; Kajii, T.
: Kabuki make-up syndrome: a syndrome of mental retardation, unusual
facies, large and protruding ears, and postnatal growth deficiency. J.
Pediat. 99: 565-569, 1981.

48. Philip, N.; Meinecke, P.; David, A.; Dean, J.; Ayme, S.; Clark,
R.; Gross-Kieselstein, E.; Hosenfeld, D.; Moncla, A.; Muller, D.;
Porteous, M.; Santos, H.; Cordeiro, I.; Selicorni, A.; Silengo, M.;
Tariverdian, G.: Kabuki make-up (Niikawa-Kuroki) syndrome: a study
of 16 non-Japanese cases. Clin. Dysmorph. 1: 63-77, 1992.

49. Selicorni, A.; Colombo, C.; Bonato, S.; Milani, D.; Giunta, A.
M.; Bedeschi, M. F.: Biliary atresia and Kabuki syndrome: another
case with long-term follow-up. (Letter) Am. J. Med. Genet. 100:
251 only, 2001.

50. Shotelersuk, V.; Punyashthiti, R.; Srivuthana, S.; Wacharasindhu,
S.: Kabuki syndrome: report of six Thai children and further phenotypic
and genetic delineation. Am. J. Med. Genet. 110: 384-390, 2002.

51. Silengo, M.; Lerone, M.; Seri, M.; Romeo, G.: Inheritance of
Niikawa-Kuroki (Kabuki makeup) syndrome. (Letter) Am. J. Med. Genet. 66:
368 only, 1996.

52. Tsukahara, M.; Kuroki, Y.; Imaizumi, K.; Miyazawa, Y.; Matsuo,
K.: Dominant inheritance of Kabuki make-up syndrome. Am. J. Med.
Genet. 73: 19-23, 1997.

53. Turner, C.; Lachlan, K.; Amerasinghe, N.; Hodgkins, P.; Maloney,
V.; Barber, J.; Temple, I. K.: Kabuki syndrome: new ocular findings
but no evidence of 8p22-p23.1 duplications in a clinically defined
cohort. Europ. J. Hum. Genet. 13: 716-720, 2005.

54. van Haelst, M. M.; Brooks, A. S.; Hoogeboom, J.; Wessels, M. W.;
Tibboel, D.; de Jongste, J. C.; den Hollander, J. C.; Bongers-Schokking,
J. J.; Niermeijer, M. F.; Willems, P. J.: Unexpected life-threatening
complications in Kabuki syndrome. Am. J. Med. Genet. 94: 170-173,
2000.

55. Wessels, M. W.; Brooks, A. S.; Hoogeboom, J.; Niermeijer, M. F.;
Willems, P. J.: Kabuki syndrome: a review study of three hundred
patients. Clin. Dysmorph. 11: 95-102, 2002.

56. White, S. M.; Thompson, E. M.; Kidd, A.; Savarirayan, R.; Turner,
A.; Amor, D.; Delatycki, M. B.; Fahey, M.; Baxendale, A.; White, S.;
Haan, E.; Gibson, K.; Halliday, J. L.; Bankier, A.: Growth, behavior,
and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki)
syndrome. Am. J. Med. Genet. 127A: 118-127, 2004.

57. Wilson, G. N.: Thirteen cases of Niikawa-Kuroki syndrome: report
and review with emphasis on medical complications and preventive management. Am.
J. Med. Genet. 79: 112-120, 1998.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Other];
Postnatal growth retardation

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Trapezoid philtrum;
[Ears];
Large prominent ears;
Recurrent otitis media in infancy;
Posteriorly rotated ears;
Hearing loss;
Preauricular pit;
[Eyes];
Long palpebral fissures;
Eversion of lateral third of lower eyelids;
Thick eyelashes;
Ptosis;
Blue sclerae;
Broad, arched eyebrows;
Sparse eyebrows;
[Nose];
Depressed nasal tip;
Short nasal columella;
[Mouth];
Cleft palate;
High-arched palate

CARDIOVASCULAR:
[Heart];
Congenital heart defect;
Ventricular septal defect;
Atrial septal defect;
[Vascular];
Coarctation of aorta

RESPIRATORY:
[Lung];
Aspiration pneumonia

ABDOMEN:
[Gastrointestinal];
Feeding difficulties;
Malabsorption;
Intestinal malrotation;
Anal stenosis;
Imperforate anus;
Anoperineal fistula

GENITOURINARY:
[External genitalia, male];
Small penis;
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Crossed fused renal ectopia;
Single fused kidneys;
[Ureters];
Ureteropelvic junction obstruction

SKELETAL:
[Spine];
Scoliosis;
Vertebral anomalies;
[Pelvis];
Congenital hip dislocations;
[Limbs];
Joint hyperextensibility;
[Hands];
Short fifth finger;
Increased digital ulnar loop and hypothenar loop patterns;
Absent digital triradius c and/or d;
Persistence of fingerpads

SKIN, NAILS, HAIR:
[Skin];
Cafe au lait spots;
[Hair];
Hirsutism

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Seizures;
Developmental delay;
Hypotonia

ENDOCRINE FEATURES:
Congenital hypothyroidism;
Premature thelarche

HEMATOLOGY:
Idiopathic thrombocytopenic purpura;
Hemolytic anemia

MISCELLANEOUS:
Increased susceptibility to infections;
Majority of cases are sporadic

MOLECULAR BASIS:
Caused by mutation in the myeloid/lymphoid or mixed lineage leukemia
2 gene (MLL2, 602113.0001)

*FIELD* CN
Kelly A. Przylepa - revised: 1/31/2001

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 10/18/2011
ckniffin: 10/17/2011
joanna: 12/12/2005
joanna: 1/15/2002
joanna: 1/31/2001

*FIELD* CN
Sonja A. Rasmussen - updated: 12/18/2013
Marla J. F. O'Neill - updated: 5/10/2012
Ada Hamosh - updated: 4/13/2012
Marla J. F. O'Neill - updated: 1/25/2012
Cassandra L. Kniffin - updated: 10/12/2011
Nara Sobreira - updated: 9/3/2010
Cassandra L. Kniffin - updated: 10/6/2008
Cassandra L. Kniffin - updated: 10/30/2007
Marla J. F. O'Neill - updated: 10/27/2006
Marla J. F. O'Neill - updated: 8/11/2006
Marla J. F. O'Neill - updated: 7/12/2005
Cassandra L. Kniffin - updated: 6/16/2005
Marla J. F. O'Neill - updated: 3/21/2005
Victor A. McKusick - updated: 1/12/2005
Victor A. McKusick - updated: 1/11/2005
Marla J. F. O'Neill - updated: 7/20/2004
Siobhan M. Dolan - updated: 7/2/2004
Marla J. F. O'Neill - updated: 6/30/2004
Victor A. McKusick - updated: 1/5/2004
Deborah L. Stone - updated: 3/21/2003
Victor A. McKusick - updated: 3/3/2003
Deborah L. Stone - updated: 10/11/2002
Sonja A. Rasmussen - updated: 3/11/2002
Sonja A. Rasmussen - updated: 6/8/2001
Victor A. McKusick - updated: 5/15/2001
Sonja A. Rasmussen - updated: 1/25/2001
Sonja A. Rasmussen - updated: 10/11/2000
Sonja A. Rasmussen - updated: 9/22/2000
Victor A. McKusick - updated: 8/17/2000
Sonja A. Rasmussen - updated: 4/24/2000
Victor A. McKusick - updated: 10/21/1999
Victor A. McKusick - updated: 5/5/1999
Victor A. McKusick - updated: 12/30/1998
Victor A. McKusick - updated: 9/18/1998
Victor A. McKusick - updated: 9/4/1998
Victor A. McKusick - updated: 12/30/1997
Victor A. McKusick - updated: 12/1/1997
Iosif W. Lurie - updated: 1/8/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 12/19/2013
carol: 12/18/2013
carol: 5/10/2012
terry: 5/10/2012
alopez: 4/13/2012
terry: 4/13/2012
carol: 1/26/2012
terry: 1/25/2012
carol: 10/14/2011
ckniffin: 10/12/2011
carol: 3/12/2011
carol: 9/3/2010
wwang: 10/13/2008
ckniffin: 10/6/2008
wwang: 11/13/2007
ckniffin: 10/30/2007
wwang: 10/27/2006
terry: 10/27/2006
wwang: 8/18/2006
terry: 8/11/2006
wwang: 7/18/2005
terry: 7/12/2005
wwang: 7/5/2005
ckniffin: 6/16/2005
ckniffin: 4/14/2005
wwang: 3/21/2005
alopez: 1/18/2005
wwang: 1/14/2005
wwang: 1/12/2005
terry: 1/11/2005
terry: 11/3/2004
carol: 7/21/2004
terry: 7/20/2004
carol: 7/6/2004
terry: 7/2/2004
carol: 7/1/2004
terry: 6/30/2004
carol: 1/20/2004
carol: 1/13/2004
cwells: 1/5/2004
tkritzer: 3/21/2003
carol: 3/5/2003
tkritzer: 3/4/2003
tkritzer: 3/3/2003
mgross: 12/10/2002
carol: 10/11/2002
terry: 3/11/2002
mcapotos: 6/12/2001
mcapotos: 6/8/2001
mcapotos: 5/23/2001
mcapotos: 5/22/2001
terry: 5/15/2001
mcapotos: 1/25/2001
mcapotos: 10/13/2000
mcapotos: 10/11/2000
mcapotos: 9/25/2000
mcapotos: 9/22/2000
mcapotos: 8/30/2000
terry: 8/17/2000
mcapotos: 5/1/2000
terry: 4/24/2000
terry: 2/28/2000
carol: 10/25/1999
terry: 10/21/1999
carol: 5/10/1999
terry: 5/5/1999
carol: 1/6/1999
terry: 12/30/1998
carol: 9/23/1998
dkim: 9/23/1998
terry: 9/18/1998
alopez: 9/9/1998
carol: 9/4/1998
mark: 2/12/1998
terry: 2/9/1998
dholmes: 12/30/1997
terry: 12/1/1997
alopez: 7/29/1997
alopez: 7/8/1997
terry: 7/7/1997
alopez: 7/3/1997
mark: 3/12/1997
jenny: 3/4/1997
jenny: 1/21/1997
jenny: 1/8/1997
mark: 2/17/1996
terry: 2/14/1996
mark: 12/20/1995
terry: 12/13/1995
terry: 11/2/1995
mimadm: 11/5/1994
davew: 8/16/1994
warfield: 3/28/1994
carol: 11/3/1993
carol: 6/3/1993

MIM 602113
*RECORD*
*FIELD* NO
602113
*FIELD* TI
*602113 MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA 2; MLL2
;;ALL1-RELATED GENE; ALR
read more*FIELD* TX

CLONING

The SET domain is a motif characteristic of proteins such as human ALL1
(159555) and Drosophila 'trithorax' (trx) and is found at the C terminus
of the 2 proteins. Using the ALL1 SET domain as a probe, Prasad et al.
(1997) cloned a novel gene, which they designated ALR (ALL1-related
gene). The gene encodes a 5,262-amino acid protein containing a SET
domain, 5 PHD fingers, potential zinc fingers, and a long run of
glutamines interrupted by hydrophobic residues (mostly leucine). They
also detected an alternatively spliced form encoding 4,957 amino acids
and lacking an N-terminal zinc finger and PHD finger. Analysis of ALR
expression showed that its approximately 18-kb transcript is expressed,
like ALL1, in most adult tissues, including a variety of hematopoietic
cells, but not in liver. Whole mount in situ hybridization of early
mouse embryos indicated expression of a similar mouse gene in multiple
tissues. Based on similarities in structure and expression pattern,
Prasad et al. (1997) concluded that ALR is likely to play a role similar
to those of ALL1 and trx.

OTHER FEATURES

By database searching, Karlin et al. (2002) identified 192 human protein
sequences that have multiple amino acid runs, many of which are
associated with disease, including cancer. Karlin et al. (2002) found
that a key aspect of 82 of these protein sequences is their role in
transcription, translation, and developmental regulation. MLL2 is a
striking example with 24 amino acid runs, all but 2 of which are
glutamine runs. Karlin et al. (2002) concluded that genes encoding a
significant number of long amino acid runs are potentially associated
with disease.

MAPPING

By analysis of rodent/human hybrid cells and analysis of the Genebridge
radiation hybrid panel, Prasad et al. (1997) mapped the ALR gene to the
12p13.1-qter region and within a 13-cR chromosome region corresponding
to a physical size of approximately 340 kb near D12S1401. Based on
information from 3 databases, they placed ALR between vitamin D receptor
(601769) at 12q12-q14 and glycerol-3-phosphate dehydrogenase (138420),
which is located in the same region. Prasad et al. (1997) noted that the
12q12-q13 region is involved in duplications and translocations
associated with cancer.

MOLECULAR GENETICS

- Kabuki Syndrome 1

Ng et al. (2010) performed the exome sequencing of 10 unrelated patients
with Kabuki syndrome (KABUK1; 147920), 7 of European ancestry, 2 of
Hispanic ancestry and 1 of mixed European and Haitian ancestry, and
identified nonsense or frameshift mutations in the MLL2 gene in 7
patients. Follow-up Sanger sequencing detected MLL2 mutations in 2 of
the 3 remaining individuals with Kabuki syndrome and in 26 of 43
additional cases. In all, they identified 33 distinct MLL2 mutations in
35 of 53 families (66%) with Kabuki syndrome (see, e.g.,
602113.0001-602113.0004). In each of 12 cases for which DNA from both
parents was available, the MLL2 variant was found to have occurred de
novo. MLL2 mutations were also identified in each of 2 families in which
Kabuki syndrome was transmitted from parent to child. None of the
additional MLL2 mutations was found in 190 control chromosomes from
individuals of matched geographic ancestry. Ng et al. (2010) suggested
that mutations in MLL2 are a major cause of Kabuki syndrome.

Hannibal et al. (2011) identified 70 mutations in the MLL2 gene in 81
(74%) of 110 kindreds with Kabuki syndrome. In simplex cases for which
DNA was available from both parents, 25 mutations were confirmed to be
de novo, whereas a transmitted mutation was found in 2 of 3 familial
cases. Most of the variants were nonsense or frameshift mutations
predicted to result in haploinsufficiency. Mutations occurred throughout
the gene, but were particularly common in exons 39 and 48. The clinical
features of those with or without mutations were similar, except for
renal anomalies, which occurred in 47% of mutation carriers compared to
14% of those who did not have a mutation.

Li et al. (2011) sequenced all 54 coding exons of the MLL2 gene in 34
patients with Kabuki syndrome and identified 18 distinct mutations in 19
patients, 11 of 12 tested de novo. Mutations were located throughout the
gene and included 3 nonsense mutations, 2 splice site mutations, 6 small
deletions or insertions, and 7 missense mutations. Li et al. (2011)
compared frequencies of clinical symptoms in MLL2 mutation carriers
versus noncarriers. MLL2 mutation carriers more often presented with
short stature and renal anomalies (p = 0.026 and 0.031, respectively),
and in addition, MLL2 showed a more typical facial gestalt (17 of 19)
compared with noncarriers (9 of 15), although this result was not
statistically significant (p = 0.1). Mutation-negative patients were
subsequently tested for mutations in 10 functional candidate genes, but
no convincing causative mutations could be identified. Li et al. (2011)
concluded that MLL2 is the major gene for Kabuki syndrome with a wide
spectrum of de novo mutations but that there is further genetic
heterogeneity accounting for MLL2 mutation-negative patients.

Banka et al. (2012) analyzed the MLL2 gene in a cohort of 116 patients
with Kabuki syndrome, including 18 patients previously reported by
Hannibal et al. (2011), and identified MLL2 variants in 74 (63.8%).
Banka et al. (2012) stated that 170 (73.2%) of 232 published MLL2
mutation-positive kabuki syndrome patients had truncating mutations.
They also noted that pathogenic missense mutations were commonly located
in exon 48.

Miyake et al. (2013) used mutation detection methods to screen 81
patients with Kabuki syndrome for MLL2 mutations and identified
mutations in 50 (61.7%); 35 of the mutations were novel. Most (70%) of
the mutations were predicted to be protein-truncating. The truncating
mutations were distributed throughout the coding region, whereas the
nontruncating mutations were most often within or adjacent to functional
domains. Patients with MLL2 truncating mutations had facies that were
more typical of those seen in the patients originally reported with
Kabuki syndrome. High-arched eyebrows, short fifth fingers and infantile
hypotonia were more commonly seen in patients with MLL2 mutations than
in those with KDM6A (300128) mutations. Only half of the patients with
MLL2 mutations had short stature and postnatal growth retardation,
compared to all of the patients with KDM6A mutations.

- Somatic Mutations

Parsons et al. (2011) identified inactivating mutations in the MLL2 gene
in approximately 10% of sequenced medulloblastomas from children.

Morin et al. (2011) found that somatic mutations in MLL2 were present in
32% of diffuse large B-cell lymphomas and 89% of follicular lymphoma
cases.

*FIELD* AV
.0001
KABUKI SYNDROME 1
MLL2, ARG5179HIS

In 2 unrelated patients with Kabuki syndrome-1 (KABUK1; 147920), Ng et
al. (2010) identified a 15536G-A transition in the MLL2 gene, resulting
in an arg5179-to-his (R5179H) substitution.

.0002
KABUKI SYNDROME 1
MLL2, LYS4527TER

In an affected parent and child with Kabuki syndrome-1 (KABUK1; 147920),
Ng et al. (2010) identified a 13580A-T transversion in the MLL2 gene,
resulting in a lys4527-to-ter (K4527X) substitution.

.0003
KABUKI SYNDROME 1
MLL2, ARG5454TER

In 2 unrelated patients with Kabuki syndrome-1 (KABUK1; 147920), Ng et
al. (2010) identified a 16360C-T transition in the MLL2 gene, resulting
in an arg5454-to-ter (R5454X) substitution.

.0004
KABUKI SYNDROME 1
MLL2, THR5464MET

In an affected parent and child and an unrelated patient with Kabuki
syndrome-1 (KABUK1; 147920), Ng et al. (2010) identified a 16391C-T
transition in the MLL2 gene, resulting in a thr5464-to-met (T5464M)
substitution.

*FIELD* RF
1. Banka, S.; Veeramachaneni, R.; Reardon, W.; Howard, E.; Bunstone,
S.; Ragge, N.; Parker, M. J.; Crow, Y. J.; Kerr, B.; Kingston, H.;
Metcalfe, K.; Chandler, K.; and 40 others: How genetically heterogeneous
is Kabuki syndrome? MLL2 testing in 116 patients, review and analyses
of mutation and phenotypic spectrum. Europ. J. Hum. Genet. 20: 381-388,
2012.

2. Hannibal, M. C.; Buckingham, K. J.; Ng, S. B.; Ming, J. E.; Beck,
A. E.; McMillin, M. J.; Gildersleeve, H. I.; Bigham, A. W.; Tabor,
H. K.; Mefford, H. C.; Cook, J.; Yoshiura, K.; and 24 others: Spectrum
of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am. J. Med.
Genet. 155A: 1511-1516, 2011.

3. Karlin, S.; Brocchieri, L.; Bergman, A.; Mrazek, J.; Gentles, A.
J.: Amino acid runs in eukaryotic proteomes and disease associations. Proc.
Nat. Acad. Sci. 99: 333-338, 2002.

4. Karlin, S.; Chen, C.; Gentles, A. J.; Cleary, M.: Associations
between human disease genes and overlapping gene groups and multiple
amino acid runs. Proc. Nat. Acad. Sci. 99: 17008-17013, 2002.

5. Li, Y.; Bogershausen, N.; Alanay, Y.; Simsek Kiper, P. O.; Plume,
N.; Keupp, K.; Pohl, E.; Pawlik, B.; Rachwalski, M.; Milz, E.; Thoenes,
M.; Albrecht, B.; and 11 others: A mutation screen in patients
with Kabuki syndrome. Hum. Genet. 130: 715-724, 2011.

6. Miyake, N.; Koshimizu, E.; Okamoto, N.; Mizuno, S.; Ogata, T.;
Nagai, T.; Kosho, T.; Ohashi, H.; Kato, M.; Sasaki, G.; Mabe, H.;
Watanabe, Y.; and 31 others: MLL2 and KDM6A mutations in patients
with Kabuki syndrome. Am. J. Med. Genet. 161A: 2234-2243, 2013.

7. Morin, R. D.; Mendez-Lago, M.; Mungall, A. J.; Goya, R.; Mungall,
K. L.; Corbett, R. D.; Johnson, N. A.; Severson, T. M.; Chiu, R.;
Field, M.; Jackman, S.; Krzywinski, M.; and 38 others: Frequent
mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476:
298-303, 2011.

8. Ng, S. B.; Bigham, A. W.; Buckingham, K. J.; Hannibal, M. C.; McMillin,
M. J.; Gildersleeve, H. I.; Beck, A. E.; Tabor, H. K.; Cooper, G.
M.; Mefford, H. C.; Lee, C.; Turner, E. H.; and 9 others: Exome
sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature
Genet. 42: 790-793, 2010.

9. Parsons, D. W.; Li, M.; Zhang, X.; Jones, S.; Leary, R. J.; Lin,
J. C.-H.; Boca, S. M.; Carter, H.; Samayoa, J.; Bettegowda, C.; Gallia,
G. L.; Jallo, G. I.; and 35 others: The genetic landscape of the
childhood cancer medulloblastoma. Science 331: 435-439, 2011.

10. Prasad, R.; Zhadanov, A. B.; Sedkov, Y.; Bullrich, F.; Druck,
T.; Rallapalli, R.; Yano, T.; Alder, H.; Croce, C. M.; Huebner, K.;
Mazo, A.; Canaani, E.: Structure and expression pattern of human
ALR, a novel gene with strong homology to ALL-1 involved in acute
leukemia and to Drosophila trithorax. Oncogene 15: 549-560, 1997.

*FIELD* CN
Sonja A. Rasmussen - updated: 12/18/2013
Marla J. F. O'Neill - updated: 5/10/2012
Ada Hamosh - updated: 4/13/2012
Marla J. F. O'Neill - updated: 1/25/2012
Cassandra L. Kniffin - updated: 10/12/2011
Ada Hamosh - updated: 9/6/2011
Ada Hamosh - updated: 3/30/2011
Nara Sobreira - updated: 9/3/2010
Patricia A. Hartz - updated: 9/26/2007
Victor A. McKusick - updated: 2/3/2003

*FIELD* CD
Victor A. McKusick: 11/10/1997

*FIELD* ED
carol: 12/19/2013
carol: 12/18/2013
carol: 5/10/2012
terry: 5/10/2012
alopez: 4/13/2012
terry: 4/13/2012
carol: 1/26/2012
terry: 1/25/2012
carol: 10/14/2011
ckniffin: 10/12/2011
alopez: 9/7/2011
terry: 9/6/2011
alopez: 3/30/2011
terry: 3/30/2011
carol: 3/12/2011
carol: 9/3/2010
mgross: 10/5/2007
mgross: 10/2/2007
terry: 9/26/2007
tkritzer: 5/7/2003
tkritzer: 2/13/2003
tkritzer: 2/6/2003
terry: 2/3/2003
carol: 2/22/1999
carol: 10/14/1998
mark: 11/10/1997