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Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.
- Source :
-
Nature genetics [Nat Genet] 2016 Aug; Vol. 48 (8), pp. 877-87. Date of Electronic Publication: 2016 Jul 11. - Publication Year :
- 2016
-
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.
- Subjects :
- Abnormalities, Multiple
Adolescent
Adult
Agenesis of Corpus Callosum genetics
Agenesis of Corpus Callosum pathology
Animals
Cerebral Cortex metabolism
Child
Child, Preschool
Chromosome Deletion
Female
Humans
Intellectual Disability genetics
Male
Mice
Middle Aged
Phenotype
Repressor Proteins metabolism
Sin3 Histone Deacetylase and Corepressor Complex
Syndrome
Young Adult
Cerebral Cortex pathology
Haploinsufficiency genetics
Intellectual Disability pathology
Methyl-CpG-Binding Protein 2 metabolism
Mutation genetics
Neurogenesis physiology
Repressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 48
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 27399968
- Full Text :
- https://doi.org/10.1038/ng.3619