19q13.41

MRD36,PP2A-Aalpha,PP2AA,PP2AAALPHA,PR65A

Wilms tumorigenesis

PP2A plays a role in the Wnt signaling pathway and has been shown to be present in the multiprotein complex containing the adenomatous polyposis coli (APC) protein, the serine/threonine kinase GSK3B, and AXIN1 (axin) (Fagotto et al., 1999; Hsu et al., 1999; Seeling et al., 1999; Ikeda et al., 2000), suggesting that PP2A has a role in regulating the activity of this complex. Overexpression of the PP2A B56 regulatory subunit has been shown to markedly reduce CTNNB1 levels in mammalian cells (Seeling et al., 1999), which suggests that increased levels of PP2A accelerate the phosphorylation-dependent proteolysis of CTNNB1. Interestingly, CTNNB1 mutations have recently been reported to occur in about 15% of Wilms tumors (Koesters et al., 1999; Maiti et al., 2000), suggesting that the APC/CTNNB1/HNF4A (Tcf)- LEF1 pathway is involved in Wilms tumorigenesis. Since PP2A also plays a role in the Wnt signaling pathway, alterations in one or more of the PP2A subunits could plausibly affect this pathway and contribute to Wilms tumorigenesis.

Mental retardation, autosomal dominant 36 (MRD36)

A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associate with impairments in adaptive behavior and manifested during the developmental period. The disease is identified 2 different de novo heterozygous missense mutation in the PPP2R1A gene (Hougo et al., 2015). The mutation were found by parent-child trio exome sequencing and confirmed by Sanger sequencing. In vitro functional expression study showed that the patients with MRD36, PPP2R1A mutation affected PP2A holoenzyme formation by variably interfering with interaction of the A-alpha subunit with the C subunit. All mutation resulted in decreased phosphatase activity, consisting with a dominant negative effect.