Relevance to Autism

Four de novo missense variants in the PPP2R5D gene were identified in seven unrelated patients with developmental delay/intellectual disability; five of these patients also presented with ASD (Shang et al., 2015). Two of the de novo PPP2R5D missense variants that were found in ASD cases in this report (p.Glu198Lys and p.Glu200Lys) have been previously identified in patients with intellectual disability (Deciphering Developmental Disorders Study, 2015; Loveday et al., 2015) and have been experimentally shown to result in reduced binding to the A and C subunits of protein phosphatase 2A (Houge et al., 2015). In addition to developmental delay/intellectual disability and, in some cases, ASD, individuals with PPP2R5D mutations frequently exhibit syndromic features including overgrowth, facial dysmorphism, and additional congenital anomalies. Oyama et al., 2022 studied 76 individuals withPPP2R5Dvariants, including 68 with pathogenic de novo variants and four siblings with a novel dominantly inherited pathogenic variant; functional analysis revealed impaired PP2A A/C-subunit binding, decreased short linear interaction motif-dependent substrate binding, or both, while the recurrent p.Glu198Lys missense variant showed the highest C-binding defect and a more severe clinical phenotype and the inherited p.Glu197Gly variant had a mild substrate binding defect. Furthermore, common clinical phenotypes of affected individuals in Oyama et al., 2022 were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%).

Molecular Function

This gene encodes a delta isoform of the regulatory subunit B56 subfamily and belongs to the phosphatase 2A regulatory subunit B family, which might modulate substrate selectivity and catalytic activity of protein phosphatase 2A, which is one of the four major Ser/Thr phosphatases and has been implicated in the negative control of cell growth and division.

External Links

References