Steric clash in the SET domain of histone methyltransferase NSD1 as a cause of sotos syndrome and its genetic heterogeneity in a Brazilian cohort

Kyungsoo Ha, Priya Anand, Jennifer A. Lee, Julie R. Jones, Chong Ae Kim, Debora Romeo Bertola, Jonathan D.J. Labonne, Lawrence C. Layman, Wolfgang Wenzel, Hyung Goo Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 may disrupt the enzymatic activity of NSD1. These results point to a structural mechanism underlying the pathology of the NSD1 missense mutations in the SET domain in Sotos syndrome. NSD1 mutations were identified in only 32% of the Brazilian Sotos patients in our study cohort suggesting other genes (including unknown disease genes) underlie the molecular etiology for the majority of these patients. Our studies also found NSD1 expression to be profound in human fetal brain and cerebellum, accounting for prenatal onset and hypoplasia of cerebellar vermis seen in Sotos syndrome.

Original languageEnglish (US)
Article number96
JournalGenes
Volume7
Issue number11
DOIs
StatePublished - Nov 2016

Fingerprint

Sotos Syndrome
Genetic Heterogeneity
Mutation
Missense Mutation
Intellectual Disability
Binding Sites
Genes
Haploinsufficiency
Molecular Dynamics Simulation
Cytoplasmic and Nuclear Receptors
Computational Biology
Methionine
Cerebellum
Lysine
Cohort Studies
histone methyltransferase
Pathology
Ligands
Brain
Proteins

Keywords

  • Histone methyltransferase
  • Intellectual disability
  • NSD1
  • SET domain
  • Sotos syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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 A.; Jones, Julie R.; Kim, Chong Ae; Bertola, Debora Romeo; Labonne, Jonathan D.J.; Layman, Lawrence C.; Wenzel, Wolfgang; Kim, Hyung Goo.

In: Genes, Vol. 7, No. 11, 96, 11.2016.

Research output: Contribution to journalArticle

Ha, Kyungsoo ; Anand, Priya ; Lee, Jennifer A. ; Jones, Julie R. ; Kim, Chong Ae ; Bertola, Debora Romeo ; Labonne, Jonathan D.J. ; Layman, Lawrence C. ; Wenzel, Wolfgang ; Kim, Hyung Goo. / Steric clash in the SET domain of histone methyltransferase NSD1 as a cause of sotos syndrome and its genetic heterogeneity in a Brazilian cohort. In: Genes. 2016 ; Vol. 7, No. 11.
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abstract = "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 may disrupt the enzymatic activity of NSD1. These results point to a structural mechanism underlying the pathology of the NSD1 missense mutations in the SET domain in Sotos syndrome. NSD1 mutations were identified in only 32{\%} of the Brazilian Sotos patients in our study cohort suggesting other genes (including unknown disease genes) underlie the molecular etiology for the majority of these patients. Our studies also found NSD1 expression to be profound in human fetal brain and cerebellum, accounting for prenatal onset and hypoplasia of cerebellar vermis seen in Sotos syndrome.",
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AU - Jones, Julie R.

AU - Kim, Chong Ae

AU - Bertola, Debora Romeo

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AU - Kim, Hyung Goo

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