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.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

“…Furthermore, RLIM acts as a co-regulator of LIM-HD containing transcription factors via the recruitment of the Sin3A/histone deacetylase co-repressor complex. Haploinsufficiency of SIN3A causes a recognizable ID syndrome with a subset of the individuals displaying ASD, seizures, microcephaly and short stature [94]. Also, pathogenic variants in the RLIMinteracting protein YY1, a zinc finger transcription factor, which is implicated in the regulation of XCI [2] in mice, cause a syndromic form of ID with behavioral disturbances, intrauterine growth restriction, and various congenital malformations, through dysregulation of key transcriptional regulators [95].…”

Principal component analysis-based unsupervised feature extraction applied to single-cell gene expression analysis1

“…E2F1 was reported to be related to postnatal brain development [37] while functional EGR1 was found in the embryonic rat brain [38]. PML and SIN3A were also reported to be involved in brain development [39] [40]. TCF3 has been shown to play a role in zebrafish brain development [41].…”

The conserved DNMT1 dependent methylation regions in human cells are vulnerable to environmental rotenone

“…Furthermore, SIN3A is recruited to the methyl-CpG binding protein MeCP2 to silence transcription. Mutations in MeCP2 cause an X-linked neurodevelopmental disorder known as Rett Syndrome and similarly impairment of SIN3A expression also causes developmental cognitive deficits (Witteveen et al 2016). MeCP2 and SIN3A have been linked to the establishment and maintenance of imprinting control regions but their effect on the expression of neighboring imprinted genes remains to be determined (Ma et al 2015).…”