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.
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
The minimal repression domain of MBD2b overlaps with the methyl-CpG-binding domain and binds directly to Sin3A
Expression of transcriptional repressor proteins mSin3A and 3B during aging and replicative senescence
Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases
MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions
Activation of Cdk2-pRB-E2F1 cell cycle pathway by repeated electroconvulsive shock in the rat frontal cortex
mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival
Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome
Tumor suppressor SMAR1 mediates cyclin D1 repression by recruitment of the SIN3/histone deacetylase 1 complex
Semaphorin 3F is a bifunctional guidance cue for dopaminergic axons and controls their fasciculation, channeling, rostral growth, and intracortical targeting
Untangling the cortex: Advances in understanding specification and differentiation of corticospinal motor neurons
Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture
Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement
Upregulation of E2F1 in cerebellar neuroprogenitor cells and cell cycle arrest during postnatal brain development
Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability
Spatiotemporal Molecular Approach of in utero Electroporation to Functionally Decipher Endophenotypes in Neurodevelopmental Disorders
The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
Development of the Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database and the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire
A novel somatic mutation of SIN3A detected in breast cancer by whole-exome sequencing enhances cell proliferation through ERα expression
Coexistence of urogenital malformations in a female fetus with de novo 15q24 microdeletion and a literature review.
In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene
A de-novo 15q24.2 deletion involving SIN3A is associated with emotional, behavioural, motor problems and hypersensitivity in a girl with above average intelligence and typical facial features.
Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder
TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons
Breakpoint Mapping of Symptomatic Balanced Translocations Links the EPHA6 , KLF13 and UBR3 Genes to Novel Disease Phenotype
The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure.
Neurodevelopmental and behavioral consequences of perinatal exposure to the HIV drug efavirenz in a rodent model
SCAPER localizes to primary cilia and its mutation affects cilia length, causing Bardet-Biedl syndrome
Gene expression changes associated with trajectories of psychopathology in a longitudinal cohort of children and adolescents.
Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling.
Rare variants in novel and known genes associated with primary angle closure glaucoma based on whole exome sequencing of 549 probands
Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.
Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients.
Convergent microstructural brain changes across genetic models of autism spectrum disorder-A pilot study
A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation.
Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes
Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.
Autism spectrum disorder is associated with challenges with social skills, repetitive behaviors, and often accompanied by sensory sensitivities and medical issues. Here is the latest research on autism.