TY - JOUR
T1 - Steric clash in the SET domain of histone methyltransferase NSD1 as a cause of sotos syndrome and its genetic heterogeneity in a Brazilian cohort
AU - Ha, Kyungsoo
AU - Anand, Priya
AU - Lee, Jennifer A.
AU - Jones, Julie R.
AU - Kim, Chong Ae
AU - Bertola, Debora Romeo
AU - Labonne, Jonathan D.J.
AU - Layman, Lawrence C.
AU - Wenzel, Wolfgang
AU - Kim, Hyung Goo
N1 - Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2016/11
Y1 - 2016/11
N2 - 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.
AB - 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.
KW - Histone methyltransferase
KW - Intellectual disability
KW - NSD1
KW - SET domain
KW - Sotos syndrome
UR - http://www.scopus.com/inward/record.url?scp=84995610922&partnerID=8YFLogxK
U2 - 10.3390/genes7110096
DO - 10.3390/genes7110096
M3 - Article
AN - SCOPUS:84995610922
SN - 2073-4425
VL - 7
JO - Genes
JF - Genes
IS - 11
M1 - 96
ER -