Relevance to Autism

A cross-trait meta-analysis of genome-wide association studies on schizophrenia (65,967 cases), bipolar disorder (41,653 cases), autism spectrum disorder (46,350 cases), ADHD (55,374 cases) and depression (688,809 cases) identified an intronic SNP in the SORCS3 gene that reached genome-wide significance for ASD following MTAG analysis (P-value 6.26E-09) (Wu et al., 2020). Other SNPs in this gene have previously been shown to reach genome-wide significance for association with ADHD (Demontis et al., 2018) and depression (Wray et al., 2018; Howard et al., 2019). A de novo nonsense variant in SORCS3 was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), and a homozygous missense variant in this gene was identified in two deceased brothers born to consanguineous parents who had presented with global developmental delay, intellectual disability, infantile spasms, microcephaly, and hypotonia (Alfadhel et al., 2018).

Molecular Function

This gene encodes a type-I receptor transmembrane protein that is a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for proprotein convertase processing, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is expressed at high levels in the brain, and candidate gene studies suggest that genetic variation in this gene is associated with Alzheimer's disease. Consistent with this observation, knockdown of the gene in cell culture results in an increase in amyloid precursor protein processing.

External Links

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