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Cited by 204Genomics and Rare DiseasesPI3K/AKT/mTOR signaling in cancerProtein Tyrosine Phosphatases

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotype relationships

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Mighell, Taylor L., Evans-Dutson, Sara, O’Roak, Brian J.·2018·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2018.03.018PMC PMC5986715

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Abstract

Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). We identified 2,273 mutations with reduced cellular lipid phosphatase activity, which includes 1,789 missense mutations. These data recapitulated known functional findings but also uncovered new insights into PTEN protein structure, biochemistry, and mutation tolerance. Several residues in the catalytic pocket showed surprising mutational tolerance. We identified that the solvent exposure of wild-type residues is a critical determinant of mutational tolerance. Further, we created a comprehensive functional map by leveraging correlations between amino acid substitutions to impute functional scores for all variants, including those not present in the assay. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD-associated mutations generally had less severe fitness scores relative to PHTS-associated mutations (p = 7.16 × 10-5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.

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  • The use of yeast for enzymatic protein functional assays relevant to endocrinologists was exemplified by study of the phosphatase encoded by PTEN, which antagonises PI3K signalling and is mutated in the PTEN Hamartoma Tumour Spectrum.

    “The use of yeast for enzymatic protein functional assays relevant to endocrinologists was exemplified by study of the phosphatase encoded by PTEN, which antagonises PI3K signalling, and which is mutated in the PTEN Hamartoma Tumour Spectrum (69).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [69]

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Cited by

Sorted by citations

Authors
Mighell, T. L., Evans-Dutson, S., & O’Roak, B. J.
Affiliations
Oregon Health & Science University (US)
Corresponding author
O’Roak, Brian J.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2018-05
Volume
102
Issue
5
Pages
943-955
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2018.03.018
PMC
PMC5986715
OpenAlex
W2794121543
Cited by
204
References
5
Citations by year
2026: 30 · 2025: 25 · 2024: 21 · 2023: 24 · 2022: 21 · 2021: 30 · 2020: 24 · 2019: 24 · 2018: 5
FWCI
12.53
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Oregon National Primate Research Center
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007680)
  • Achievement Rewards for College Scientists Foundation
  • Brain and Behavior Research Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • Alfred P. Sloan Foundation (FG-2015-65608)
  • Atherton Family Foundation
  • Simons Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
PTEN, lipid phosphatase activity, saturation mutagenesis, genotype-phenotype correlation, PTEN hamartoma tumor syndrome, autism spectrum disorder, missense mutations, mutational tolerance, catalytic pocket, solvent exposure, tumor suppressor mutations, hypomorphic mutation
MeSH terms
Alleles, Humans, Mutation, Cluster Analysis, Mutagenesis, PTEN Phosphohydrolase, Genetic Association Studies, High-Throughput Nucleotide Sequencing

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