Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease

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dc.contributor.authorTorices, Leire
dc.contributor.authorMingo, Janire
dc.contributor.authorRodríguez Escudero, María Isabel
dc.contributor.authorFernández-Acero Bascones, Teresa
dc.contributor.authorLuna, Sandra
dc.contributor.authorNunes-Xavier, Caroline E.
dc.contributor.authorLópez, José I.
dc.contributor.authorMercadillo, Fátima
dc.contributor.authorCurrás, María
dc.contributor.authorUrioste, Miguel
dc.contributor.authorMolina Martín, María
dc.contributor.authorJiménez Cid, Víctor
dc.contributor.authorPulido, Rafael
dc.date.accessioned2024-01-10T13:11:59Z
dc.date.available2024-01-10T13:11:59Z
dc.date.issued2023-05
dc.description.abstractHeterozygous 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.
dc.description.departmentDepto. de Microbiología y Parasitología
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipPTEN Research Foundation (United Kingdom)
dc.description.sponsorshipMinisterio de Economía y Competitividad (Spain and The European Regional Development Fund)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipEuropean Structural and Investment Funds
dc.description.sponsorshipAsociación Española Contra el Cáncer
dc.description.sponsorshipGobierno Vasco, Departamento de Educación
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.statuspub
dc.identifier.citationTorices 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.
dc.identifier.doi10.1038/s41431-022-01265-w
dc.identifier.essn1476-5438
dc.identifier.issn1018-4813
dc.identifier.officialurlhttps://doi.org/10.1038/s41431-022-01265-w
dc.identifier.urihttps://hdl.handle.net/20.500.14352/92258
dc.issue.number5
dc.journal.titleEur J Hum Genet.
dc.language.isoeng
dc.page.final577
dc.page.initial568
dc.relation.projectIDinfo:eu-repo/grantAgreement/CP20/00008
dc.relation.projectIDinfo:eu-repo/grantAgreement/BBH-19-001
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/SAF2016-79847-R
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/PID2019-105342GB-I00
dc.relation.projectIDinfo:eu-repo/grantAgreement/S2017/ BMD‐3691
dc.relation.projectIDinfo:eu-repo/grantAgreement/PRE_2014_1_285
dc.relation.projectIDinfo:eu-repo/grantAgreement/CP20/00008
dc.rights.accessRightsrestricted access
dc.subject.cdu615.28
dc.subject.keywordPTEN
dc.subject.keywordPHTS
dc.subject.keywordYeast
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmMicrobiología (Farmacia)
dc.subject.ucmParasitología (Farmacia)
dc.subject.unesco24 Ciencias de la Vida
dc.titleFunctional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease
dc.typejournal article
dc.type.hasVersionAM
dc.volume.number31
dspace.entity.typePublication
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