Kleefstra syndrome (Homo sapiens)

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7, 851021, 3, 4, 6, 958119q34.37q36.1Coffin-Sirus syndromeHistone methylation activity,transcriptional coactivationChromatin remodellingMethylated DNA bindingquestionedNuclear receptor recruiting chromatin modifying complexes2q23.1 microdeletion syndromeKleefstra syndrome 1Kleefstra syndrome 28EHMT1KDM6AKMT2CNCOA6NR1I3L-lysine residueSMARCD2Polycomb repressive deubiquitinase(PR-DUB) complexPAXIP1MBD5Zn(2+)ASH2LS-adenosyl-L-homocysteineRBBP5SMARCC1SMARCD1Histone H3.3DPY30SMARCA4SWI/SNF complexS-adenosyl-L-methionineSMARCB1ASXL1ACTL6AN6-methyl-L-lysine residueSMARCD3N6-methyl-L-lysine residueRXRAN6,N6-dimethyl-L-lysine residueHistone modificationsSMARCA2WDR5ACTL6BBAP1ARID1AARID1BSMARCC2BIX-01294DNASMARCB1ASC-2/NCOA6 complex(ASCOM)8PAGR1KMT2CS-adenosyl-L-methionineS-adenosyl-L-homocysteine2


Description

Kleefstra syndrome is a rare genetic disorder (MIM #610253, Orpha:261494). The cause was found first to be a deletion in the region 9q34.2 with the main gene EHMT1, which is a histone methyltransferase and involved in epigenetics, namely histone methylation on histone H3 lysine residues. It also methylates DNA. Similar phenotypes were later found with loss of function mutations in other proteins involved in histone methylation, namely KMT2C (MLL3) located on 7q36.1, MBD5, SMARCB1, and NR1I3 (MIM #617768 Kleefstra syndrome 2).

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Ontology Terms

 

Bibliography

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  1. Shinsky SA, Monteith KE, Viggiano S, Cosgrove MS; ''Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation.''; J Biol Chem, 2015 PubMed Europe PMC Scholia
  2. Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y; ''A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells.''; Science, 2002 PubMed Europe PMC Scholia
  3. Goo YH, Sohn YC, Kim DH, Kim SW, Kang MJ, Jung DJ, Kwak E, Barlev NA, Berger SL, Chow VT, Roeder RG, Azorsa DO, Meltzer PS, Suh PG, Song EJ, Lee KJ, Lee YC, Lee JW; ''Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins.''; Mol Cell Biol, 2003 PubMed Europe PMC Scholia
  4. Park SH, Ayoub A, Lee YT, Xu J, Kim H, Zheng W, Zhang B, Sha L, An S, Zhang Y, Cianfrocco MA, Su M, Dou Y, Cho US; ''Cryo-EM structure of the human MLL1 core complex bound to the nucleosome.''; Nat Commun, 2019 PubMed Europe PMC Scholia
  5. Baymaz HI, Fournier A, Laget S, Ji Z, Jansen PW, Smits AH, Ferry L, Mensinga A, Poser I, Sharrocks A, Defossez PA, Vermeulen M; ''MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domain.''; Proteomics, 2014 PubMed Europe PMC Scholia
  6. Chang Y, Ganesh T, Horton JR, Spannhoff A, Liu J, Sun A, Zhang X, Bedford MT, Shinkai Y, Snyder JP, Cheng X; ''Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases.''; J Mol Biol, 2010 PubMed Europe PMC Scholia
  7. Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K; ''PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex.''; J Biol Chem, 2007 PubMed Europe PMC Scholia
  8. van Nuland R, Smits AH, Pallaki P, Jansen PW, Vermeulen M, Timmers HT; ''Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes.''; Mol Cell Biol, 2013 PubMed Europe PMC Scholia
  9. Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, Turner A, Wilson M, McGaughran J, Rauch A, Zenker M, Adam MP, Innes M, Davies C, López AG, Casalone R, Weber A, Brueton LA, Navarro AD, Bralo MP, Venselaar H, Stegmann SP, Yntema HG, van Bokhoven H, Brunner HG; ''Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.''; J Med Genet, 2009 PubMed Europe PMC Scholia
  10. Zhang P, Lee H, Brunzelle JS, Couture JF; ''The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases.''; Nucleic Acids Res, 2012 PubMed Europe PMC Scholia
  11. Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE, Wissink-Lindhout W, Fenckova M, van den Akker WM, Kasri NN, Nillesen WM, Prescott T, Clark RD, Devriendt K, van Reeuwijk J, de Brouwer AP, Gilissen C, Zhou H, Brunner HG, Veltman JA, Schenck A, van Bokhoven H; ''Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability.''; Am J Hum Genet, 2012 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
134654view09:19, 24 July 2024EgonwCompleted a datasource
134454view00:07, 22 July 2024EweitzRefine legend, standardize case
134453view00:03, 22 July 2024EweitzOntology Term : 'Coffin-Siris syndrome' added !
126041view12:32, 29 March 2023Fehrhartadded missing ID
126040view12:29, 29 March 2023FehrhartOntology Term : 'altered histone modification pathway' added !
126039view12:29, 29 March 2023FehrhartOntology Term : 'Kleefstra syndrome 2' added !
126038view12:28, 29 March 2023FehrhartOntology Term : 'Kleefstra syndrome 1' added !
126037view12:28, 29 March 2023FehrhartOntology Term : 'Kleefstra syndrome' added !
126036view12:28, 29 March 2023FehrhartOntology Term : 'disease pathway' added !
126035view12:26, 29 March 2023FehrhartNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACTL6AGeneProductENSG00000136518 (Ensembl)
ACTL6BGeneProductENSG00000077080 (Ensembl)
ARID1AGeneProductENSG00000117713 (Ensembl)
ARID1BGeneProductENSG00000049618 (Ensembl)
ASC-2/NCOA6 complex (ASCOM)ComplexCPX-7091
ASH2LGeneProductENSG00000129691 (Ensembl)
ASXL1GeneProductENSG00000171456 (Ensembl)
BAP1GeneProductENSG00000163930 (Ensembl)
BIX-01294Metabolite93986 (ChEBI) 6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine
DNAMetaboliteCHEBI:16991 (ChEBI)
DPY30GeneProductENSG00000162961 (Ensembl)
EHMT1GeneProductENSG00000181090 (Ensembl)
Histone H3.3GeneProductP84243 (Uniprot-TrEMBL)
Histone modificationsPathwayWP2369 (WikiPathways)
KDM6AGeneProductENSG00000147050 (Ensembl)
KMT2CGeneProductMLL3
KMT2CGeneProductENSG00000055609 (Ensembl) MLL3
L-lysine residueMetabolite29969 (ChEBI)
MBD5GeneProductENSG00000204406 (Ensembl)
N6,N6-dimethyl-L-lysine residueMetabolite61976 (ChEBI)
N6-methyl-L-lysine residueMetabolite61929 (ChEBI)
NCOA6GeneProductENSG00000198646 (Ensembl)
NR1I3GeneProductENSG00000143257 (Ensembl)
PAGR1GeneProductENSG00000280789 (Ensembl)
PAXIP1GeneProductENSG00000157212 (Ensembl)
Polycomb repressive deubiquitinase (PR-DUB) complexComplex
RBBP5GeneProductENSG00000117222 (Ensembl)
RXRAGeneProductENSG00000186350 (Ensembl)
S-adenosyl-L-homocysteineMetabolite57856 (ChEBI)
S-adenosyl-L-methionineMetabolite59789 (ChEBI)
SMARCA2GeneProductENSG00000080503 (Ensembl)
SMARCA4GeneProductENSG00000127616 (Ensembl)
SMARCB1GeneProductENSG00000099956 (Ensembl)
SMARCC1GeneProductENSG00000173473 (Ensembl)
SMARCC2GeneProductENSG00000139613 (Ensembl)
SMARCD1GeneProductENSG00000066117 (Ensembl)
SMARCD2GeneProductENSG00000108604 (Ensembl)
SMARCD3GeneProductENSG00000082014 (Ensembl)
SWI/SNF complexComplex
WDR5GeneProductENSG00000196363 (Ensembl)
Zn(2+)Metabolite29105 (ChEBI)

Annotated Interactions

SourceTargetTypeDatabase referenceComment
KMT2Cmim-catalysis60264 (Rhea)
N6-methyl-L-lysine residueN6,N6-dimethyl-L-lysine residuemim-conversion60284 (Rhea)
S-adenosyl-L-methionineS-adenosyl-L-homocysteinemim-conversion60284 (Rhea)
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