Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort.
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 analyzedNSD1in 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 theNSD1missense mutations in the SET domain in Sotos syndrome.NSD1mutations 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.
Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA. kyungsooha1@gmail.com.|New drug development center, Osong Medical Innovation Foundation, 28160 Cheongju, Korea. kyungsooha1@gmail.com.
Kyungsoo
K
Ha
Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), 76344 Karlsruhe, Germany. priya.anand@kit.edu.
Priya
P
Anand
Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA. jalee@ggc.org.
Jennifer A
JA
Lee
Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA. juliejones@ggc.org.
Julie R
JR
Jones
Unit of Clinical Genetics, Instituto da Criança, FMUSP, São Paulo 05403-000, Brazil. chong.kim@hc.fm.usp.br.
Chong Ae
CA
Kim
Unit of Clinical Genetics, Instituto da Criança, FMUSP, São Paulo 05403-000, Brazil. debora.bertola@hc.fm.usp.br.
Debora Romeo
DR
Bertola
Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA. molgenetics_and_epigenetics@hotmail.com.
Jonathan D J
JD
Labonne
Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA. lalayman@augusta.edu.|Neuroscience Program, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA. lalayman@augusta.edu.
Lawrence C
LC
Layman
Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), 76344 Karlsruhe, Germany. wolfgang.wenzel@kit.edu.
Wolfgang
W
Wenzel
Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA. hkim@augusta.edu.
Hyung-Goo
HG
Kim
NSD1; SET domain; Sotos syndrome; histone methyltransferase; intellectual disability