A de novo loss-of-function (LoF) variant in the SRCAP gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second ASD-associated de novo LOF variant was identified in a proband from the Autism Simplex Collection (TASC) in Stessman et al., 2017. A third de novo LoF variant in SRACP was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Additional de novo loss-of-function and missense variants in the SRCAP gene were observed in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; furthermore, a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified SRCAP as a gene reaching exome-wide significance (P < 2.5E-06). Rots et al., 2021 reported 33 unrelated individuals with truncating SRCAP variants proximal (n=28) or distal (n=5) to the locus for Floating-Harbor syndrome who presented with a distinct neurodevelopmental disorder characterized by developmental delay with or without intellectual disability, behavioral and psychiatric abnormalities, non-specific facial features, musculoskeletal abnormalities, and hypotonia; autism spectrum disorder was observed in individuals with both proximal SRCAP variants (10/24; 41.67%) and distal SRCAP variants (2/5; 40%) in this report.
Molecular Function
This gene encodes the core catalytic component of the multiprotein chromatin-remodeling SRCAP complex. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It can function as a transcriptional activator in Notch-mediated, CREB-mediated and steroid receptor-mediated transcription. Mutations in this gene cause Floating-Harbor syndrome (OMIM 136140), a rare disorder characterized by short stature, language deficits and dysmorphic facial features.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature
SRCAP is associated with ASD, and the heterozygous knockout mouse model shows autism-like phenotypes such as deficits in social behavior and increased repetitive behaviors, as well as seizure susceptibility and cognitive impairments. Overexpression of SATB2 in newborns restores all phenotypes in adulthood.
References
Type
Title
Author, Year
Primary
Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Srcap heterozygous mice were generated using CRISPR-Cas9 technology. The design targeted exon 4 of Srcap. An allele with an 8-nt deletion in exon 4 was selected as the knockout allele for studies.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not reported
Mutant ES Cell Line: Model Source: Zilong Qiu lab
Description: There was a significant reduction in parvalbumin-positive neurons within the retrosplenial cortex and hippocampal dentate gyrus regions of heterozygous mice.
Exp Paradigm: Parvalbumin
Description: Heterozygous mice show reduced inhibitory synapses represented by immunostaining of Gephyrin in the retrosplenial cortex and dentate gyrus regions.
Miniature post synaptic current frequency: inhibitory1
Decreased
Description: Heterozygous mice exhibited a lower frequency of mIPSCs and mEPSCs in the dentate gyrus region than wildtype mice, though their amplitude remained unchanged.
Miniature post synaptic current frequency: excitatory1
Decreased
Description: Heterozygous mice exhibited a lower frequency of mIPSCs and mEPSCs in the dentate gyrus region than wildtype mice, though their amplitude remained unchanged.
Description: After ChIP with an anti-H2A.z antibody, only qPCR with ChIP primer set two yielded positive signals and also revealed reduced H2A.z protein at the 291-bp promoter region of Satb2 in heterozygous mice.
