RT Journal Article
SR Electronic
T1 A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 255265
DO 10.1101/255265
A1 Taylor L. Mighell
A1 Sara Evans-Dutson
A1 Brian j. O’Roak
YR 2018
UL http://biorxiv.org/content/early/2018/01/30/255265.abstract
AB 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). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. 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.