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

TitleMulti-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction.
Publication TypeJournal Article
Year of Publication2020
AuthorsPost KL, Belmadani M, Ganguly P, Meili F, Dingwall R, McDiarmid TA, Meyers WM, Herrington C, Young BP, Callaghan DB, Rogic S, Edwards M, Niciforovic A, Cau A, Rankin CH, O'Connor TP, Bamji SX, Loewen CJR, Allan DW, Pavlidis P, Haas K
JournalNat Commun
Volume11
Issue1
Pagination2073
Date Published2020 Apr 29
ISSN2041-1723
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.

URLhttps://doi.org/10.1038/s41467-020-15943-0
DOI10.1038/s41467-020-15943-0
Alternate JournalNat Commun
PubMed ID32350270
PubMed Central IDPMC7190743
Grant List573845 / / Simons Foundation /
FDN-148468 / / Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre) /