Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN hamartoma tumour syndrome.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Tibarewal Priyanka, Rathbone Victoria, Conduit Sarah E, Classen Gala Anastasia Electra, Black Fiona, Danesh Mohammad Amin, Constantinou Georgia, Asgarian Zeinab, Tohyama Koujiro, Kriplani Nisha, Garcia Virginia Alvarez, Foxall Elizabeth, Belarbi Djenat, Leverve Marie, Pearce Wayne, Adil Mahreen, Varyova Zofia, Conde Lucia, Alves Adriana, Masson Glenn R, Williams Roger L, Flanagan Adrienne M, Herrero Javier, Mohamed Isra Ahmed, Stroud Katerina, Tischkowitz Marc, Lachlan Katherine, Scudamore Cheryl L, Scott Mark G H, Leslie Nicholas R, Kessaris Nicoletta, Vanhaesebroeck Bart
Аннотация
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 generated Pten+/R173C mice which developed few tumours during their lifetime, aligning with normal PI3K/AKT signalling. However, they exhibited lymphoid hyperplasia, macrocephaly and brain abnormalities, associated with impaired nuclear functions of PTEN-R173C, demonstrated by reduced dsDNA damage repair. We integrated PHTS patient data with our mouse model results, and 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.