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

Kathryn L. Post, Manuel Belmadani, Payel Ganguly, Fabian Meili, Riki Dingwall, Troy A. McDiarmid, Warren M. Meyers, Caitlin Herrington, Barry P. Young, Daniel B. Callaghan, Sanja Rogic, Matthew Edwards, Ana Niciforovic, Alessandro Cau, Catharine H. Rankin, Timothy P. O’Connor, Shernaz X. Bamji, Christopher J. R. Loewen, Douglas W. Allan, Paul Pavlidis () and Kurt Haas ()
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Kathryn L. Post: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Manuel Belmadani: Department of Psychiatry, University of British Columbia
Payel Ganguly: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Fabian Meili: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Riki Dingwall: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Troy A. McDiarmid: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Warren M. Meyers: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Caitlin Herrington: Department of Cellular and Physiological Sciences, University of British Columbia
Barry P. Young: Department of Cellular and Physiological Sciences, University of British Columbia
Daniel B. Callaghan: Department of Psychiatry, University of British Columbia
Sanja Rogic: Department of Psychiatry, University of British Columbia
Matthew Edwards: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Ana Niciforovic: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Alessandro Cau: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Catharine H. Rankin: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Timothy P. O’Connor: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Shernaz X. Bamji: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Christopher J. R. Loewen: Department of Cellular and Physiological Sciences, University of British Columbia
Douglas W. Allan: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Paul Pavlidis: Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Kurt Haas: Djavad Mowafaghian Centre for Brain Health, University of British Columbia

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15943-0

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