Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

Josefine S Witteveen; Marjolein H Willemsen; Thaís C D Dombroski; Nick H M van Bakel; Willy M Nillesen; Josephus A van Hulten; Eric J R Jansen; Dave Verkaik; Hermine E Veenstra-Knol; Conny M A van Ravenswaaij-Arts; Jolien S Klein Wassink-Ruiter; Marie Vincent; Albert David; Cedric Le Caignec; Jolanda Schieving; Christian Gilissen; Nicola Foulds; Patrick Rump; Tim Strom; Kirsten Cremer; Alexander M Zink; Hartmut Engels; Sonja A de Munnik; Jasper E Visser; Han G Brunner; Gerard J M Martens; Rolph Pfundt; Tjitske Kleefstra; Sharon M Kolk

doi:10.1038/ng.3619

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Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

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Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

Josefine S Witteveen, Marjolein H Willemsen, Thaís C D Dombroski, Nick H M van Bakel, Willy M Nillesen, Josephus A van Hulten, Eric J R Jansen, Dave Verkaik, Hermine E Veenstra-Knol, Conny M A van Ravenswaaij-Arts, …

Nature genetics, Vol.48(8), pp.877-887

01/08/2016

DOI: https://doi.org/10.1038/ng.3619

PMID: 27399968

Résumé

Abnormalities, Multiple

Adolescent

Adult

Agenesis of Corpus Callosum - genetics

Agenesis of Corpus Callosum - pathology

Animals

Cerebral Cortex - metabolism

Cerebral Cortex - pathology

Child

Child, Preschool

Chromosome Deletion

Female

Haploinsufficiency - genetics

Humans

Intellectual Disability - genetics

Intellectual Disability - pathology

Male

Methyl-CpG-Binding Protein 2 - metabolism

Mice

Middle Aged

Mutation - genetics

Neurogenesis - physiology

Phenotype

Repressor Proteins - genetics

Repressor Proteins - metabolism

Syndrome

Young Adult

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.

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Titre: Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity
Créateurs - sans rôle: Josefine S Witteveen - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Marjolein H Willemsen - Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands
Thaís C D Dombroski - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Nick H M van Bakel - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Willy M Nillesen - Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands
Josephus A van Hulten - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Eric J R Jansen - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Dave Verkaik - Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands
Hermine E Veenstra-Knol - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Conny M A van Ravenswaaij-Arts - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Jolien S Klein Wassink-Ruiter - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Marie Vincent - Centre Hospitalier Universitaire de Nantes
Albert David - Centre Hospitalier Universitaire de Nantes
Cedric Le Caignec - Inserm
Jolanda Schieving - Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
Christian Gilissen - Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands
Nicola Foulds - Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
Patrick Rump - Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Tim Strom - Institute of Human Genetics, Technische Universität München, Munich, Germany
Kirsten Cremer - University of Bonn
Alexander M Zink - Institute of Human Genetics, University of Bonn, Bonn, Germany
Hartmut Engels - University of Bonn
Sonja A de Munnik - Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands
Jasper E Visser - Department of Neurology, Amphia Hospital Breda, Berda, the Netherlands
Han G Brunner - Radboud University Medical Center
Gerard J M Martens - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Rolph Pfundt - Radboud University Medical Center
Tjitske Kleefstra - Radboud University Medical Center
Sharon M Kolk - Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands
Détails de publication: Nature genetics, Vol.48(8), pp.877-887
Identifiants: 99158807909311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article