Inherited PTEN mutations and the prediction of phenotype. (April 2016)

• Record Type: Journal Article
• Authors: Leslie, Nicholas R.; Longy, Michel
• Is Part Of: Seminars in cell & developmental biology. Volume 52(2016)
• Page Start: 30
• Page End: 38
• Publication Date: 2016-04
• Subjects: PTEN -- Phosphatase -- Tumour suppressor -- Mutation -- Cancer -- Autism spectrum disorder; Cytology -- Periodicals; Developmental biology -- Periodicals; 571.6
• DOI: 10.1016/j.semcdb.2016.01.030
• Languages: English
• ISSNs: 1084-9521

Abstract

Graphical abstract: Highlights: Loss of function PTEN mutations drive both sporadic tumours and genetic disorders. PTEN mutation carriers have complex disease with high variability of expressivity. Phenotypes include developmental, neurological, and benign and malignant neoplasms. Partially active PTEN links more strongly to autism spectrum disorder. Catalytically inactive mutant PTEN links more strongly to tumour phenotypes. Abstract: PTEN has been heavily studied due to its role as a tumour suppressor and as a core inhibitory component of the phosphoinositide 3-kinase (PI3K) signalling network. It is a broadly expressed phosphatase which displays complexity and diversity in both its functions and regulation and accordingly, in the laboratory numerous classes of functionally distinct mutations have been generated. Inherited loss of function mutations in the PTEN gene were originally identified in sufferers of Cowden disease, but later shown to associate with more diverse human pathologies, mostly relating to cell and tissue overgrowth, leading to the use of the broader term, PTEN Hamartoma Tumour Syndrome. Recent phenotypic analysis of clinical cohorts of PTEN mutation carriers, combined with laboratory studies of the consequences of these mutations implies that stable catalytically inactive PTEN mutants may lead to the most severe phenotypes, and conversely, that mutants retaining partial function associate more frequently with a milder phenotype, with autism spectrum disorder often being diagnosed. Future work will be needed to confirm and to refine these genotype–phenotype relationships and convert this developing knowledge into improved patient management and potentially treatment with emerging drugs which target the PI3K pathway.