De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism

Abstract

Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3β)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID.

Keywords: Autism spectrum disorder; De novo mutations; Intellectual disabilities; PPP2R5D; Protein phosphatase; Whole-exome sequencing.

Figure 1. Facial characteristics of individuals with PPP2R5D variants

A. Individual 1, B. Individual 3, C. Individual 7

Figure 2. Effects of E420K mutation in PPP2R5D

Both panels show the molecular surfaces of the regulatory and catalytic subunit of PPP2R5D, calculated from homology models (see Methods). The surface of the catalytic subunit is colored green. The surface of the regulatory subunit is colored according to electrostatic potential with red regions indicating electronegative regions and blue indicating electropositive regions. Panel A shows the surface of the wild-type regulatory subunit, and Panel B shows the surface of the E420K mutant. The active site cavity of the catalytic subunit is labeled with a “C”