Cargando…

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 K...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126782/
https://www.ncbi.nlm.nih.gov/pubmed/27834868
http://dx.doi.org/10.3390/genes7110096
_version_ 1782470166514237440
author 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
author_facet 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
author_sort Ha, Kyungsoo
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5126782
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-51267822016-12-02 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 Genes (Basel) Article 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. MDPI 2016-11-09 /pmc/articles/PMC5126782/ /pubmed/27834868 http://dx.doi.org/10.3390/genes7110096 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
title Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort
title_full Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort
title_fullStr Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort
title_full_unstemmed Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort
title_short Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort
title_sort steric clash in the set domain of histone methyltransferase nsd1 as a cause of sotos syndrome and its genetic heterogeneity in a brazilian cohort
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126782/
https://www.ncbi.nlm.nih.gov/pubmed/27834868
http://dx.doi.org/10.3390/genes7110096
work_keys_str_mv AT hakyungsoo stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT anandpriya stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT leejennifera stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT jonesjulier stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT kimchongae stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT bertoladeboraromeo stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT labonnejonathandj stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT laymanlawrencec stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT wenzelwolfgang stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort
AT kimhyunggoo stericclashinthesetdomainofhistonemethyltransferasensd1asacauseofsotossyndromeanditsgeneticheterogeneityinabraziliancohort