Relevance to Autism

Whole-exome sequencing of 198 unrelated individuals with ASD/ID in Novelli et al., 2020 identified eight different heterozygous germline mutations (including one that was recurrent in three unrelated patients) in the WWP1 gene in 10 ASD probands; variants in WWP1 were subsequently shown to be preferentially enriched in ASD/ID probands compared to European populations in gnomAD (p < 0.00001; OR = 30.6 (95% CI 16.27-57.59)) and a cohort of 1158 individuals from the Italian general population (p < 0.00001; OR = 19.93 (95% CI 5.47-72.90)). Two of the missense variants identified in ASD probands in Novelli et al., 2020 (p.Arg86His and p.Asn745Ser) had previously been shown in Lee et al., 2020 to induce increased PTEN polyubiquitination compared to wild-type WWP1, consistent with a gain-of-function effect.

Molecular Function

WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 4 tandem WW domains and a HECT (homologous to the E6-associated protein carboxyl terminus) domain. The encoded protein belongs to a family of NEDD4-like proteins, which are E3 ubiquitin-ligase molecules and regulate key trafficking decisions, including targeting of proteins to proteosomes or lysosomes.

External Links

References