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Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort

Ha, Kyungsoo; Anand, Priya; Lee, Jennifer; Jones, Julie; Kim, Chong; Bertola, Debora; Labonne, Jonathan; Layman, Lawrence; Wenzel, Wolfgang; Kim, Hyung-Goo

Most histone methyltransferases (HMTase) harbor a predicted Su(var)3–9, Enhancer-of-zeste, Trithorax (SET) domain, which transfers a methyl group to a lysine residue in their substrates. Mutations of the SET domains were reported to cause intellectual disability syndromes such as Sotos, Weaver, or Kabuki syndromes. Sotos syndrome is an overgrowth syndrome with intellectual disability caused by haploinsufficiency of the nuclear receptor binding SET domain protein 1 (NSD1) gene, an HMTase at 5q35.2–35.3. Here, we analyzed NSD1 in 34 Brazilian Sotos patients and identified three novel and eight known mutations. Using protein modeling and bioinformatic approaches, we evaluated the effects of one novel (I2007F) and 21 previously reported missense mutations in the SET domain. For the I2007F mutation, we observed conformational change and loss of structural stability in Molecular Dynamics (MD) simulations which may lead to loss-of-function of the SET domain. For six mutations near the ligand-binding site we observed in simulations steric clashes with neighboring side chains near the substrate S-Adenosyl methionine (SAM) binding site, which ... mehr

Zugehörige Institution(en) am KIT Institut für Nanotechnologie (INT)
Publikationstyp Zeitschriftenaufsatz
Jahr 2016
Sprache Englisch
Identifikator DOI: 10.3390/genes7110096
ISSN: 2073-4425
URN: urn:nbn:de:swb:90-661376
KITopen ID: 1000066137
Erschienen in Genes
Band 7
Heft 11
Seiten Art. Nr.: 96
Lizenz CC BY 4.0: Creative Commons Namensnennung 4.0 International
Schlagworte Sotos syndrome, NSD1, SET domain, histone methyltransferase, intellectual disability
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