Fig E8.
Effect of PHLPP2 polymorphism p.L1016S in patients with pathogenic PTEN mutations. A, Sanger sequencing of wild-type and c.3047T>C (p.L1016S) variants. B, LightScanner analysis. C, PHLPP2 genotype-phenotype analysis. Sixty-six patients with PHTS were analyzed for the L1016S variant and autoimmune and lymphoid hyperplasia phenotype. Potential gene-gene interaction between PTEN and PHLPP2 was investigated by determining whether the hypomorphic polymorphism in PHLPP2 (p.L1016S) with reduced dephosphorylation activity at the C-terminal hydrophobic motif Ser473 of AKTE9 has a detectable effect on the immune phenotype in patients with PHTS. The p.L1016S variant is present in about one fifth of the human populationE9 and was similarly frequently detected in the PHTS cohort. Although there is no literature to suggest that this polymorphism has major relevance for the development of autoimmunity in the general population with wild-type PTEN, we hypothesized that this polymorphism could be relevant for patients who harbor a pathogenic PTEN mutation and would therefore likely have a different PI3K-AKT signal activation threshold. There was a nonsignificant trend toward an increased frequency of autoimmunity and no significant difference in lymphoid hyperplasia between patients with PHTS with wild-type or L1016S variants. Our data suggest that heterozygous loss of PHLPP2 phosphatase activity has a potential effect on autoimmunity in those patients, but despite analysis of 66 patients with PHTS, this is underpowered.