title: Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.
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.
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Josefine S
authors.initials: JS
authors.lastname: Witteveen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Thaís C D
authors.initials: TC
authors.lastname: Dombroski
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Nick H M
authors.initials: NH
authors.lastname: van Bakel
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Josephus A
authors.initials: JA
authors.lastname: van Hulten
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Eric J R
authors.initials: EJ
authors.lastname: Jansen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Verkaik
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Hermine E
authors.initials: HE
authors.lastname: Veenstra-Knol
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Conny M A
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jolien S Klein
authors.initials: JS
authors.lastname: Wassink-Ruiter
authors.affiliation: Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France.
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.affiliation: Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France.|Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, INSERM UMRS 957, Nantes, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Schieving
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Christian
authors.identifier: 0000-0003-1693-9699
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Wessex Clinical Genetics Services, University Hospital Southampton National Health Service Foundation Trust, Princess Anne Hospital, Southampton, UK.|Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Foulds
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rump
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Zink
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Sonja A
authors.initials: SA
authors.lastname: de Munnik
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.|Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Neurology, Amphia Hospital Breda, Berda, the Netherlands.
authors.forename: Jasper E
authors.initials: JE
authors.lastname: Visser
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Gerard J M
authors.initials: GJ
authors.lastname: Martens
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
authors.forename: Sharon M
authors.identifier: 0000-0003-2116-5456
authors.initials: SM
authors.lastname: Kolk
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D061085:Agenesis of Corpus Callosum / Q000235:genetics / Q000473:pathology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D055495:Neurogenesis / Q000502:physiology*; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013577:Syndrome; D055815:Young Adult
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D056264:Sin3 Histone Deacetylase and Corepressor Complex