Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

Nat Commun. 2020 Apr 29;11(1):2073. doi: 10.1038/s41467-020-15943-0.


Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Caenorhabditis elegans / physiology
  • Cells, Cultured
  • Dendrites / physiology
  • Disease / genetics*
  • Drosophila / genetics
  • Drosophila / growth & development
  • Enzyme Assays
  • HEK293 Cells
  • Humans
  • Models, Genetic*
  • Mutation, Missense / genetics*
  • Neoplasms / genetics
  • Nervous System / growth & development
  • PTEN Phosphohydrolase / genetics*
  • Phosphorylation
  • Protein Stability
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyramidal Cells / metabolism
  • Rats, Sprague-Dawley
  • Saccharomyces cerevisiae / metabolism


  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase