A pathogenic role for germline PTEN variants which accumulate into the nucleus.

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dc.contributor.authorMingo, Janire
dc.contributor.authorRodríguez Escudero, María Isabel
dc.contributor.authorLuna, Sandra
dc.contributor.authorFernández Acero, Teresa
dc.contributor.authorAmo, Laura
dc.contributor.authorJonasson, Amy R
dc.contributor.authorZori, Roberto T
dc.contributor.authorLópez, José I
dc.contributor.authorMolina, María
dc.contributor.authorCid, Víctor J.
dc.contributor.authorPulido, Rafael
dc.date.accessioned2023-06-17T13:23:51Z
dc.date.available2023-06-17T13:23:51Z
dc.date.issued2018-04-30
dc.description.abstractThe PTEN gene encodes a master regulator protein that exerts essential functions both in the cytoplasm and in the nucleus. PTEN is mutated in the germline of both patients with heterogeneous tumor syndromic diseases, categorized as PTEN hamartoma tumor syndrome (PHTS), and a group affected with autism spectrum disorders (ASD). Previous studies have unveiled the functional heterogeneity of PTEN variants found in both patient cohorts, making functional studies necessary to provide mechanistic insights related to their pathogenicity. Here, we have functionally characterized a PTEN missense variant [c.49C>G; p.(Gln17Glu); Q17E] associated to both PHTS and ASD patients. The PTEN Q17E variant displayed partially reduced PIP3-catalytic activity and normal stability in cells, as shown using S. cerevisiae and mammalian cell experimental models. Remarkably, PTEN Q17E accumulated in the nucleus, in a process involving the PTEN N-terminal nuclear localization sequence. The analysis of additional germline-associated PTEN N-terminal variants illustrated the existence of a PTEN N-terminal region whose targeting in disease causes PTEN nuclear accumulation, in parallel with defects in PIP3-catalytic activity in cells. Our findings highlight the frequent occurrence of PTEN gene mutations targeting PTEN N-terminus whose pathogenicity may be related, at least in part, with the retention of PTEN in the nucleus. This could be important for the implementation of precision therapies for patients with alterations in the PTEN pathway.en
dc.description.departmentDepto. de Microbiología y Parasitología
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía, Comercio y Empresa (España)
dc.description.sponsorshipGobierno Vasco
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/55638
dc.identifier.citationMingo, J., Rodríguez Escudero, M. I., Luna, S. et al. «A Pathogenic Role for Germline PTEN Variants Which Accumulate into the Nucleus». European Journal of Human Genetics, vol. 26, n.o 8, agosto de 2018, pp. 1180-87. DOI.org (Crossref), https://doi.org/10.1038/s41431-018-0155-x.
dc.identifier.doi10.1038/s41431-018-0155-x
dc.identifier.issn1476-5438
dc.identifier.officialurlhttps://www.nature.com/
dc.identifier.officialurlhttps//doi.org/10.1038/s41431-018-0155-x
dc.identifier.urihttps://hdl.handle.net/20.500.14352/13361
dc.journal.titleEuropean journal of human genetics
dc.language.isoeng
dc.page.final1187
dc.page.initial1180
dc.publisherSpringer Nature
dc.relation.projectID(SAF2013-48812-R, SAF2016-79847-R, BIO2013-44112-P, and BIO2016-75030-P)
dc.relation.projectID2013111011
dc.rightsAtribución 3.0 España
dc.rights.accessRightsopen access
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/es/
dc.subject.cdu579
dc.subject.ucmMicrobiología (Farmacia)
dc.subject.unesco3302.03 Microbiología Industrial
dc.titleA pathogenic role for germline PTEN variants which accumulate into the nucleus.en
dc.typejournal article
dc.volume.number26
dspace.entity.typePublication
relation.isAuthorOfPublication9f72eaa3-3210-4d9b-a54a-087d7f01ef0f
relation.isAuthorOfPublication.latestForDiscovery9f72eaa3-3210-4d9b-a54a-087d7f01ef0f
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