RT Journal Article
T1 Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease
A1 Torices, Leire
A1 Mingo, Janire
A1 Rodríguez Escudero, María Isabel
A1 Fernández-Acero Bascones, Teresa
A1 Luna, Sandra
A1 Nunes-Xavier, Caroline E.
A1 López, José I.
A1 Mercadillo, Fátima
A1 Currás, María
A1 Urioste, Miguel
A1 Molina Martín, María
A1 Jiménez Cid, Víctor
A1 Pulido, Rafael
AB Heterozygous germline mutations in PTEN gene predispose to hamartomas and tumors in different tissues, as well as to neurodevelopmental disorders, and define at genetic level the PTEN Hamartoma Tumor Syndrome (PHTS). The major physiologic role of PTEN protein is the dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), counteracting the pro-oncogenic function of phosphatidylinositol 3-kinase (PI3K), and PTEN mutations in PHTS patients frequently abrogate PTEN PIP3 catalytic activity. PTEN also displays non-canonical PIP3-independent functions, but their involvement in PHTS pathogeny is less understood. We have previously identified and described, at clinical and genetic level, novel PTEN variants of unknown functional significance in PHTS patients. Here, we have performed an extensive functional characterization of these PTEN variants (c.77 C > T, p.(Thr26Ile), T26I; c.284 C > G, p.(Pro95Arg), P95R; c.529 T > A, p.(Tyr177Asn), Y177N; c.781 C > G, p.(Gln261Glu), Q261E; c.829 A > G, p.(Thr277Ala), T277A; and c.929 A > G, p.(Asp310Gly), D310G), including cell expression levels and protein stability, PIP3-phosphatase activity, and subcellular localization. In addition, caspase-3 cleavage analysis in cells has been assessed using a C2-domain caspase-3 cleavage-specific anti-PTEN antibody. We have found complex patterns of functional activity on PTEN variants, ranging from loss of PIP3-phosphatase activity, diminished protein expression and stability, and altered nuclear/cytoplasmic localization, to intact functional properties, when compared with PTEN wild type. Furthermore, we have found that PTEN cleavage at the C2-domain by the pro-apoptotic protease caspase-3 is diminished in specific PTEN PHTS variants. Our findings illustrate the multifaceted molecular features of pathogenic PTEN protein variants, which could account for the complexity in the genotype/phenotype manifestations of PHTS patients.
SN 1018-4813
YR 2023
FD 2023-05
LK https://hdl.handle.net/20.500.14352/92258
UL https://hdl.handle.net/20.500.14352/92258
LA eng
NO Torices L, Mingo J, Rodríguez-Escudero I, Fernández-Acero T, Luna S, Nunes-Xavier CE, et al. Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease. Eur J Hum Genet 2023;31:568–77. https://doi.org/10.1038/s41431-022-01265-w.
NO PTEN Research Foundation (United Kingdom)
NO Ministerio de Economía y Competitividad (Spain and The European Regional Development Fund)
NO Comunidad de Madrid
NO European Structural and Investment Funds
NO Asociación Española Contra el Cáncer
NO Gobierno Vasco, Departamento de Educación
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 4 ago 2024