The spliceosome in autism spectrum disorder

A homozygous mutation in the WBP4 gene resulted in an absence of the WBP4 protein in an 8-year-old patient from Hadassah Medical Center. The proband`s phenotype is neurodevelopmental delay and autism spectrum disorder (ASD) - a brain development condition that impacts how a person socializes. WBP4 is a spliceosome subunit, which catalyzes pre-mRNA splicing. While mutations in the WBP4 gene have not been reported, the connection between abnormal pre-mRNA splicing and ASD is well established. Analysis of ASD individuals` post-mortem brain transcriptome revealed a greater change in splicing than that of gene expression. It is speculated that this deviation from precise gene expression is the cause of atypical brain development. RNAseq of the proband`s fibroblasts (WBP4-/-) and his consanguineous parents (WBP4+/-) identified 1,104 differential alternative splicing events, the majority (587) in genes related to abnormal nervous system physiology. Interestingly we identified an enrichment of intron retention events (312 of 1,104). Our preliminary results point to this group of introns as significantly shorter with higher GC content. Furthermore, the PAX5 transcription factor, whose mutations are associated with ASD, was found to be enriched in the retained introns and is hypothesized to remove introns synergistically with WBP4. Overexpressing WBP4 in WBP4 -/- fibroblasts abolished abnormal splicing. By studying the importance of WBP4 as part of the spliceosome in neurodevelopment, we hope to shed light on the process of alternative splicing in the nervous system.