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

doi:10.3390/genes7110096

Kyungsoo Ha, Wolfgang Wenzel + Show 8 more

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https://doi.org/10.3390/genes7110096

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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.

Highlights

Sotos syndrome (MIM 117550), known as cerebral gigantism with intellectual disability and delayed development of motor skills, was initially described in 1964, and hundreds of cases have been subsequently reported [1,2,3,4,5]
The bioinformatics approach confirmed the existence of other domains, including one SET domain at amino acid position 1942–2065, two PWWP domains at positions 323–388 and 1756–1818, one associated with SET (AWS) domain at position 1890–1940 and one Post–SET domain at position
The presence of the three major criteria and several other conditions associated with Sotos syndrome allow us to infer a clinical diagnosis of typical Sotos syndrome, the genetic analysis of the nuclear receptor binding SET domain protein 1 (NSD1) gene is considered another criterion for the confirmation of the molecular diagnosis

Summary

Introduction

Sotos syndrome (MIM 117550), known as cerebral gigantism with intellectual disability and delayed development of motor skills, was initially described in 1964, and hundreds of cases have been subsequently reported [1,2,3,4,5]. Most reported cases have been sporadic, but occasional familial cases have demonstrated that Sotos syndrome is autosomal dominant [6,7]. Identification of a causative gene was necessary for the precise genetic diagnosis and understanding of the molecular and physiological basis of Sotos syndrome. In 2002, positional cloning in a Sotos syndrome individual with a balanced translocation, t(5;8)(q35;q24.1), resulted in the identification of a nuclear receptor binding SET domain protein. Over 400 different mutations in NSD1 associated with Sotos syndrome have been reported.

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