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Witteveen, J.S.* ; Willemsen, M.H.* ; Dombroski, T.C.* ; van Bakel, N.H.* ; Nillesen, W.M.* ; van Hulten, J.A.* ; Jansen, E.J.* ; Verkaik, D.* ; Veenstra-Knol, H.E.* ; van Ravenswaaij-Arts, C.M.* ; Wassink-Ruiter, J.S.* ; Vincent, M.* ; David, A.* ; Le Caignec, C.* ; Schieving, J.* ; Gilissen, C.* ; Foulds, N.* ; Rump, P.* ; Strom, T.M. ; Cremer, K.* ; Zink, A.M.* ; Engels, H.* ; de Munnik, S.A.* ; Visser, J.E.* ; Brunner, H.G.* ; Martens, G.J.* ; Pfundt, R.* ; Kleefstra, T.* ; Kolk, S.M.*

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

Nat. Genet. 48, 877-887 (2016)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Developing Cerebral-cortex; 15q24 Microdeletion Syndrome; Histone Deacetylase Complex; Embryonic Stem-cells; Neural Stem; Neurodevelopmental Disorders; Developing Neocortex; Rett-syndrome; Human Brain; Mecp2
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 48, Issue: 8, Pages: 877-887 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)