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

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.

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

“…A murine model of germlinemislocalized cytoplasm-predominant PTEN exhibits macrocephaly and a neurocognitive profile reminiscent of high-functioning ASD (92,93). Intriguingly, germline-mislocalized nuclear-predominant PTEN can exist in patients with either cancer or ASD (57,94). In this context, it is tempting to speculate whether mutant nuclear PTEN plays distinct roles in the affected tissues related to the latter disparate phenotypes.…”

PTEN in Autism and Neurodevelopmental Disorders

“…ASD-related PTEN mutations function mostly in a dominant-negative manner resulting in an unstable but catalytically active gene product, but can also lead to altered subcellular localization. For example, whereas most of the PHTS-linked PTEN mutations are loss-of-function mutations in line with loss of PTEN's canonical tumor-suppressive role, other ASD-associated mutations lead to impaired nucleocytoplasmic shuttling (Rodríguez-Escudero et al 2011;Tilot et al 2014;Spinelli et al 2015;Fricano-Kugler et al 2018;Mingo et al 2018).…”

PTEN in Hereditary and Sporadic Cancer

“…A murine model of germline-mislocalized cytoplasm-predominant Pten exhibits macrocephaly and a neurocognitive profile reminiscent of high-functioning ASD (Tilot et al 2014(Tilot et al , 2016. Intriguingly, germline-mislocalized nuclear-predominant PTEN can exist in patients with either cancer or ASD (He et al 2011a;Mingo et al 2018). In this context, it is tempting to speculate whether mutant nuclear PTEN plays distinct roles in an organ-specific manner related to the seemingly disparate phenotypes.…”

“…Sporadic melanomas frequently have a loss of PTEN through LOH, deletion, and mutation (Trotman and Pandolfi 2003). PTEN can also be epigenetically silenced in melanoma, as decreased PTEN transcript levels were associated with PTEN promoter methylation (Mirmohammadsadegh et al 2006). In mice, Pten deletion in pigmented mouse cells does not lead to the development of melanomas but did increase the number of melanocytes that led to melanoma formation in half of the samples when topical carcinogen was added (Mirmohammadsadegh et al 2006).…”

“…PTEN can also be epigenetically silenced in melanoma, as decreased PTEN transcript levels were associated with PTEN promoter methylation (Mirmohammadsadegh et al 2006). In mice, Pten deletion in pigmented mouse cells does not lead to the development of melanomas but did increase the number of melanocytes that led to melanoma formation in half of the samples when topical carcinogen was added (Mirmohammadsadegh et al 2006). In the presence of other genetic alterations such as BRAF and Cdkn2a, Pten can contribute to the malignant phenotype (You et al 2002;Dankort et al 2009).…”