Abstract
Phosphate and tensin homolog on chromosome ten (PTEN) germline mutations are associated with an overarching condition known as PTEN hamartoma tumor syndrome. Clinical phenotypes associated with this syndrome range from macrocephaly and autism spectrum disorder to Cowden syndrome, which manifests as multiple noncancerous tumor-like growths (hamartomas), and an increased predisposition to certain cancers. It is unclear, however, the basis by which mutations might lead to these very diverse phenotypic outcomes. Here we show that, by considering the molecular consequences of mutations in PTEN on protein structure and function, we can accurately distinguish PTEN mutations exhibiting different phenotypes. Changes in phosphatase activity, protein stability, and intramolecular interactions appeared to be major drivers of clinical phenotype, with cancer-associated variants leading to the most drastic changes, while ASD and non-pathogenic variants associated with more mild and neutral changes, respectively. Importantly, we show via saturation mutagenesis that more than half of variants of unknown significance could be associated with disease phenotypes, while over half of Cowden syndrome mutations likely lead to cancer. These insights can assist in exploring potentially important clinical outcomes delineated by PTEN variation.
Highlights
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual-specificity phosphatase, and powerful tumor suppressor, with additional lipid dephosphorylation properties within the PI3K/AKT/mTOR signalling pathway
To ensure that curation of pathogenic mutations was as comprehensive as possible, specific studies detailing large clinical PTEN hamartoma tumor syndrome (PHTS), Cowden Syndrome (CS), or Bannayan-Riley-Ruvalcaba syndrome (BRRS) cohorts obtained from the Cleveland Clinic [38,39], and a list of autism spectrum disorder (ASD) and cancer mutations curated by Spinelli et al [40], were used as a final check
Observing the spatial distribution of the main mutation classes within the gene and subsequent structure (Fig. 3) shows that, while mutations associated with either cancer or ASD were widely distributed across the whole gene, those causing cancer were more enriched within the phosphatase domain, which mediates its tumor suppressive function
Summary
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual-specificity phosphatase, and powerful tumor suppressor, with additional lipid dephosphorylation properties within the PI3K/AKT/mTOR signalling pathway. It is responsible for the dephosphorylation of PIP3 to PIP2, blocking cell division mediated by AKT. PTEN is 403aa long and composed of two main domains (Fig. 1): (i) the phosphatase domain (N-terminus; residues 1–185), which contains the protein tyrosine phosphatase (PTP) conserved signature motif (HCXXGXXR) responsible for its dual-specificity phosphatase activity and lipid binding site [3,4], and (ii) the C2 domain (C-terminus; residues 186–403), which contains a disordered loop spanning residues 286–309 [4,5] (Fig. 1).
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