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

Autor: Witteveen JS; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands., Willemsen MH; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Dombroski TC; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands., van Bakel NH; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands., Nillesen WM; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., van Hulten JA; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands., Jansen EJ; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands., Verkaik D; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Veenstra-Knol HE; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., van Ravenswaaij-Arts CM; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Wassink-Ruiter JS; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Vincent M; Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France., David A; Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, Nantes, France., Le Caignec C; 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., Schieving J; Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands., Gilissen C; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Foulds N; 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., Rump P; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Strom T; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Institute of Human Genetics, Technische Universität München, Munich, Germany., Cremer K; Institute of Human Genetics, University of Bonn, Bonn, Germany., Zink AM; Institute of Human Genetics, University of Bonn, Bonn, Germany., Engels H; Institute of Human Genetics, University of Bonn, Bonn, Germany., de Munnik SA; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Visser JE; 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., Brunner HG; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Martens GJ; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands., Pfundt R; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Kleefstra T; Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, the Netherlands., Kolk SM; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2016 Aug; Vol. 48 (8), pp. 877-87. Date of Electronic Publication: 2016 Jul 11.
DOI: 10.1038/ng.3619
Abstrakt: 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.
Databáze: MEDLINE
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