Distinguishing between PTEN clinical phenotypes through mutation analysis

[Display omitted] •This work links mechanistic effects of mutations and different phenotypes in PTEN.•Distinct PTEN diseases lie on a spectrum of changes in protein stability and function.•Computational analysis could accurately distinguish between PTEN phenotypes.. Phosphate and tensin homolog on c...

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Bibliographic Details
Published in:Computational and structural biotechnology journal 2021-01, Vol.19, p.3097-3109
Main Authors: Portelli, Stephanie, Barr, Lucy, de Sá, Alex G.C., Pires, Douglas E.V., Ascher, David B.
Format: Article
Language:English
Subjects:
Genotype-phenotype correlations
Machine learning
Mutation analysis
PHTS
PTEN
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Summary:[Display omitted] •This work links mechanistic effects of mutations and different phenotypes in PTEN.•Distinct PTEN diseases lie on a spectrum of changes in protein stability and function.•Computational analysis could accurately distinguish between PTEN phenotypes.. 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.
ISSN:2001-0370
2001-0370
DOI:10.1016/j.csbj.2021.05.028