Next Article in Journal
Gene Therapy: A Paradigm Shift in Dentistry
Previous Article in Journal
Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence
Article Menu

Export Article

Open AccessArticle
Genes 2016, 7(11), 96; doi:10.3390/genes7110096

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

1
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
2
New drug development center, Osong Medical Innovation Foundation, 28160 Cheongju, Korea
3
Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), 76344 Karlsruhe, Germany
4
Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA
5
Unit of Clinical Genetics, Instituto da Criança, FMUSP, São Paulo 05403-000, Brazil
6
Neuroscience Program, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Roel Ophoff
Received: 1 August 2016 / Revised: 8 October 2016 / Accepted: 21 October 2016 / Published: 9 November 2016
(This article belongs to the Section Human Genomics and Genetic Diseases)
View Full-Text   |   Download PDF [3355 KB, uploaded 9 November 2016]   |  

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. View Full-Text
Keywords: Sotos syndrome; NSD1; SET domain; histone methyltransferase; intellectual disability Sotos syndrome; NSD1; SET domain; histone methyltransferase; intellectual disability
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Ha, K.; Anand, P.; Lee, J.A.; Jones, J.R.; Kim, C.A.; Bertola, D.R.; Labonne, J.D.J.; Layman, L.C.; Wenzel, W.; Kim, H.-G. Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort. Genes 2016, 7, 96.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Genes EISSN 2073-4425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top