Intellectual disability (ID) is a genetic disorder characterized by limitations in intellectual capabilities, such as below-average cognitive functioning and deficiencies in social and practical skills, which affects 1-2% of the world population (Hu et al., 2015). A recent study by Houge et al. presented information on cases of ID that identified de novo missense mutations in two subunits of protein phosphatase 2A (PP2A), a heterotrimeric enzyme consisting of a catalytic subunit (C), a regulatory subunit (B, B’, B’’, and B’’’), and a scaffolding subunit (A) that regulates a variety of cellular functions. The mutations were found in the PPP2R5D gene that encodes for the B subunit and the PPP2R1A gene that encodes for the Aα subunit. Patients with the Aα mutations (P179L, R182W, and R258H) displayed phenotypic characteristics such as hypotonia, absence of speech, and inability to walk unsupported. The study proposed the three Aα PPP2R1A mutations cause a dominant-negative function associated with lost or diminished A-C subunit binding affinity and loss of A-B subunit binding affinity of multiple regulatory subunits, with the notable exception of B’δ (Houge et al., 2015). Binding assays of the three Aα mutations with Cα and Bβ2 and B’β showed evidence to support that the de novo mutations have a negative effect on the binding affinity of the PP2A holoenzyme. This data supports previous claims about the effects of these mutations on PP2A.
Clint McDaniel, ’17
Biochemistry & Molecular Biology