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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Post 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 Kdoi
10.1038/s41467-020-15943-0subject
Has Abstractpub_date
2020-04-29 00:00:00pages
2073issue
1issn
2041-1723pii
10.1038/s41467-020-15943-0journal_volume
11pub_type
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