Abstract
The 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.
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Acknowledgements
This work was supported in part by grants SAF2013-48812-R, SAF2016-79847-R, BIO2013-44112-P, and BIO2016-75030-P from Ministerio de Economía y Competitividad (Spain), and grant 2013111011 from Gobierno Vasco, Departamento de Salud (Basque Country, Spain). JM was supported by a predoctoral grant from Gobierno Vasco (Programa de Formación de Personal Investigador no doctor, Departamento de Educación, Política Lingüística y Cultura del Gobierno Vasco). SL has been the recipient of a fellowship from Bilbao Bizkaia Kutxa (BBK) (Spain). We thank Prof. Johan T. den Dunnen for providing database submission support.
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Mingo, J., Rodríguez-Escudero, I., Luna, S. et al. A pathogenic role for germline PTEN variants which accumulate into the nucleus. Eur J Hum Genet 26, 1180–1187 (2018). https://doi.org/10.1038/s41431-018-0155-x
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DOI: https://doi.org/10.1038/s41431-018-0155-x
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