Kleefstra syndrome (WP5351)
Homo sapiens
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).
Authors
Friederike Ehrhart , Eric Weitz , and Egon WillighagenActivity
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Organisms
Homo sapiensCommunities
Diseases Rare DiseasesAnnotations
Disease Ontology
Coffin-Siris syndrome Kleefstra syndrome 2 Kleefstra syndrome 1 Kleefstra syndromePathway Ontology
disease pathway altered histone modification pathway| Label | Type | Compact URI | Comment |
|---|---|---|---|
| S-adenosyl-L-methionine | Metabolite | chebi:59789 | |
| N6-methyl-L-lysine residue | Metabolite | chebi:61929 | |
| L-lysine residue | Metabolite | chebi:29969 | |
| Zn(2+) | Metabolite | chebi:29105 | |
| N6,N6-dimethyl-L-lysine residue | Metabolite | chebi:61976 | |
| BIX-01294 | Metabolite | chebi:93986 | 6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-[1-(phenylmethyl)-4-piperidinyl]-4-quinazolinamine |
| S-adenosyl-L-homocysteine | Metabolite | chebi:57856 | |
| DNA | Metabolite | chebi:16991 | |
| ARID1B | GeneProduct | ensembl:ENSG00000049618 | |
| SMARCA4 | GeneProduct | ensembl:ENSG00000127616 | |
| SMARCC1 | GeneProduct | ensembl:ENSG00000173473 | |
| SMARCC2 | GeneProduct | ensembl:ENSG00000139613 | |
| SMARCD1 | GeneProduct | ensembl:ENSG00000066117 | |
| SMARCD2 | GeneProduct | ensembl:ENSG00000108604 | |
| SMARCD3 | GeneProduct | ensembl:ENSG00000082014 | |
| ACTL6A | GeneProduct | ensembl:ENSG00000136518 | |
| ACTL6B | GeneProduct | ensembl:ENSG00000077080 | |
| EHMT1 | GeneProduct | ensembl:ENSG00000181090 | |
| RXRA | GeneProduct | ensembl:ENSG00000186350 | |
| ASH2L | GeneProduct | ensembl:ENSG00000129691 | |
| ASXL1 | GeneProduct | ensembl:ENSG00000171456 | |
| NCOA6 | GeneProduct | ensembl:ENSG00000198646 | |
| MBD5 | GeneProduct | ensembl:ENSG00000204406 | |
| KDM6A | GeneProduct | ensembl:ENSG00000147050 | |
| DPY30 | GeneProduct | ensembl:ENSG00000162961 | |
| RBBP5 | GeneProduct | ensembl:ENSG00000117222 | |
| PAXIP1 | GeneProduct | ensembl:ENSG00000157212 | |
| KMT2C | GeneProduct | ensembl:ENSG00000055609 | MLL3 |
| NR1I3 | GeneProduct | ensembl:ENSG00000143257 | |
| WDR5 | GeneProduct | ensembl:ENSG00000196363 | |
| ARID1A | GeneProduct | ensembl:ENSG00000117713 | |
| SMARCB1 | GeneProduct | ensembl:ENSG00000099956 | |
| BAP1 | GeneProduct | ensembl:ENSG00000163930 | |
| Histone H3.3 | GeneProduct | uniprot:P84243 | |
| SMARCA2 | GeneProduct | ensembl:ENSG00000080503 | |
| PAGR1 | GeneProduct | ensembl:ENSG00000280789 |
References
- A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Ogawa H, Ishiguro KI, Gaubatz S, Livingston DM, Nakatani Y. Science. 2002 May 10;296(5570):1132–6. PubMed Europe PMC Scholia
- Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins. Goo YH, Sohn YC, Kim DH, Kim SW, Kang MJ, Jung DJ, et al. Mol Cell Biol. 2003 Jan;23(1):140–9. PubMed Europe PMC Scholia
- PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, et al. J Biol Chem. 2007 Jul 13;282(28):20395–406. PubMed Europe PMC Scholia
- Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, et al. J Med Genet. 2009 Sep;46(9):598–606. PubMed Europe PMC Scholia
- Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases. Chang Y, Ganesh T, Horton JR, Spannhoff A, Liu J, Sun A, et al. J Mol Biol. 2010 Jul 2;400(1):1–7. PubMed Europe PMC Scholia
- The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases. Zhang P, Lee H, Brunzelle JS, Couture JF. Nucleic Acids Res. 2012 May;40(9):4237–46. PubMed Europe PMC Scholia
- Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LELM, et al. Am J Hum Genet. 2012 Jul 13;91(1):73–82. PubMed Europe PMC Scholia
- Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. van Nuland R, Smits AH, Pallaki P, Jansen PWTC, Vermeulen M, Timmers HTM. Mol Cell Biol. 2013 May;33(10):2067–77. PubMed Europe PMC Scholia
- MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domain. Baymaz HI, Fournier A, Laget S, Ji Z, Jansen PWTC, Smits AH, et al. Proteomics. 2014 Oct;14(19):2179–89. PubMed Europe PMC Scholia
- Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation. Shinsky SA, Monteith KE, Viggiano S, Cosgrove MS. J Biol Chem. 2015 Mar 6;290(10):6361–75. PubMed Europe PMC Scholia
- Cryo-EM structure of the human MLL1 core complex bound to the nucleosome. Park SH, Ayoub A, Lee YT, Xu J, Kim H, Zheng W, et al. Nat Commun. 2019 Dec 5;10(1):5540. PubMed Europe PMC Scholia