PTEN-opathies: from biological insights to evidence-based precision medicine
Lamis Yehia, … , Joanne Ngeow, Charis Eng
Lamis Yehia, … , Joanne Ngeow, Charis Eng
Published January 7, 2019
Citation Information: J Clin Invest. 2019;129(2):452-464. https://doi.org/10.1172/JCI121277.
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Review Series

PTEN-opathies: from biological insights to evidence-based precision medicine

Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the “PTEN-opathies.” Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Authors

Lamis Yehia, Joanne Ngeow, Charis Eng

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Figure 3

PTEN structure and germline mutation spectrum in PHTS.

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PTEN structure and germline mutation spectrum in PHTS. (A) PTEN germline...
(A) PTEN germline mutation spectrum from 431 PHTS patients. PTEN is canonically a 403–amino acid protein. Different types of mutations are depicted in the lollipop plot overlaying the PTEN protein structure. The frequency of mutations correlates with the heights of the vertical lines representing each lollipop. PTEN comprises a PIP2-binding domain (PBD), a phosphatase domain, a C2 domain, and a C-terminal tail including a PDZ-binding domain. The active site is included within amino acid residues 123 and 130. (B) PTEN consists of 9 exons that encode the 403–amino acid protein. The exons are overlaid to match the protein domains in A. Intronic regions are not represented. The colored bars represent large deletions (abbreviated as del) and duplications (abbreviated as dup) annotated by affected exon numbers and the number of affected patients in parentheses. Figure adapted with permission from ref. 174.