Tibarewal, Priyanka;
Rathbone, Victoria;
Conduit, Sarah E;
Classen, Gala Anastasia Electra;
Black, Fiona;
Danesh, Mohammad Amin;
Constantinou, Georgia;
... Vanhaesebroeck, Bart; + view all
(2025)
Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN Hamartoma Tumour Syndrome.
Disease Models & Mechanisms
, Article dmm.052527. 10.1242/dmm.052527.
(In press).
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Abstract
PTEN Hamartoma Tumour Syndrome (PHTS), a rare disease caused by germline heterozygous PTEN mutations, is associated with multi-organ/tissue overgrowth, autism spectrum disorder and increased cancer risk. Phenotypic variability in PHTS is partly due to diverse PTEN mutations and the protein's multifaceted functions. PTEN is primarily a PIP3 phosphatase regulating PI3K/AKT signalling but also maintains chromosomal stability through nuclear functions such as double-strand (ds) DNA damage repair. Here we show that PTEN-R173C, a pathogenic variant frequently found in PHTS and somatic cancer, has elevated PIP3 phosphatase activity that effectively regulates canonical PI3K/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. We generated Pten+/R173C mice which developed few tumours during their lifetime, aligning with normal PI3K/AKT signalling. However, they exhibit lymphoid hyperplasia, macrocephaly and brain abnormalities, associated with impaired nuclear functions of PTEN-R173C, demonstrated by reduced dsDNA damage repair. Integrating PHTS patient data with our mouse-model, we propose that defective nuclear functions of PTEN variants can predict the onset of PHTS phenotypes, and that late-onset cancer in these individuals may arise from secondary genetic alterations, facilitated by compromised dsDNA repair.
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