Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN hamartoma tumour syndrome.

ABSTRACT: PTEN hamartoma tumour syndrome (PHTS), a rare disease caused by germline heterozygous PTEN variants, is associated with multi-organ/tissue overgrowth, autism spectrum disorder and increased cancer risk. Phenotypic variability in PHTS is partly due to diverse PTEN variants and the protein's multifaceted functions. PTEN is primarily a phosphatidylinositol(3,4,5)trisphosphate (PIP3) phosphatase regulating PI3K/AKT signalling but also maintains chromosomal stability through nuclear functions such as double-stranded (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

SUBMITTER: Tibarewal P 

PROVIDER: S-EPMC12817337 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature