Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN Hamartoma Tumour Syndrome

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.