A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

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Abstract

ABSTRACT 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.

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