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

Nat Genet. 2016 Aug;48(8):877-87. doi: 10.1038/ng.3619.

Josefine S Witteveen ¹, Marjolein H Willemsen ², Thaís C D Dombroski ¹, Nick H M van Bakel ¹, Willy M Nillesen ², Josephus A van Hulten ¹, Eric J R Jansen ¹, Dave Verkaik ², Hermine E Veenstra-Knol ³, Conny M A van Ravenswaaij-Arts ³, Jolien S Klein Wassink-Ruiter ³, Marie Vincent ⁴, Albert David ⁴, Cedric Le Caignec ⁴ ⁵, Jolanda Schieving ⁶, Christian Gilissen ², Nicola Foulds ⁷ ⁸, Patrick Rump ³, Tim Strom ⁹ ¹⁰, Kirsten Cremer ¹¹, Alexander M Zink ¹¹, Hartmut Engels ¹¹, Sonja A de Munnik ², Jasper E Visser ¹ ⁶ ¹², Han G Brunner ², Gerard J M Martens ¹, Rolph Pfundt ², Tjitske Kleefstra ², Sharon M Kolk ¹

Affiliations

1 Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
2 Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
3 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
4 Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France.
5 Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, INSERM UMRS 957, Nantes, France.
6 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
7 Wessex Clinical Genetics Services, University Hospital Southampton National Health Service Foundation Trust, Princess Anne Hospital, Southampton, UK.
8 Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
9 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
10 Institute of Human Genetics, Technische Universität München, Munich, Germany.
11 Institute of Human Genetics, University of Bonn, Bonn, Germany.
12 Department of Neurology, Amphia Hospital Breda, Berda, the Netherlands.

PMID: 27399968 DOI: 10.1038/ng.3619

Abstract

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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