Two novel missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disease caused by mutations in serine threonine kinase 11 () and characterized by an increased risk of developing cancer. Inactivation of has been associated with the mammalian target of rapamycin (mTOR) pathway. Hyperactivation and phosphorylation of the key downstream target genes ribosomal protein S6 kinase 1 (S6K1) and S6 promote protein synthesis and cell proliferation. To better understand the effects of dysfunction in the pathogenesis of PJS, genomic DNA samples from 21 patients with PJS from 11 unrelated families were investigated for mutations in the present study. The results revealed 6 point mutations and 2 large deletions in 8 (72.7%, 8/11) of the unrelated families. Notably, 3 novel mutations were identified, which included 2 missense mutations [c.88G>A (p.Asp30Asn) and c.869T>C (p.Leu290Pro)]. Subsequent immunohistochemical analysis revealed staining for phosphorylated-S6 protein in colonic hamartoma and breast benign tumor tissues from patients with PJS carrying the two respective missense mutations. Additionally, the novel missense mutants induced phosphorylation of S6K1 and S6, determined using western blot analysis, and promoted the proliferation of HeLa and SW1116 cells, determined using Cell Counting Kit-8 and colony formation assays. Collectively, these findings extend the mutation spectrum and confirm the pathogenicity of two novel missense mutations. This study represents a valuable insight into the molecular mechanisms implicated in the pathogenesis of PJS.