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 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.

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Publication Details

Journal
Disease Models & Mechanisms
Published
2025-11-11
DOI
https://doi.org/10.1242/dmm.052527
Citations
2
Primary Topic
PI3K/AKT/mTOR signaling in cancer
Type
article
Field-Weighted Citation Impact
1.61
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article

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

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2 citations
Disease Models & Mechanisms
PI3K/AKT/mTOR signaling in cancer
1.61
article

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

Koujiro Tohyama, Georgia Constantinou, Priyanka Tibarewal, Zeinab Asgarian, Nicoletta Kessaris, Roger Williams, Lucía Conde, Victoria Rathbone, Marie Leverve, Nisha Kriplani, Mahreen Adil, Cheryl L. Scudamore, Javier Herrero, Bart Vanhaesebroeck, Marc Tischkowitz, Glenn R. Masson, Elizabeth Foxall, Katherine Lachlan, Sarah E. Conduit, Fiona Black, Nicholas R. Leslie, Adriana Terezinha Neves Novellino Alves, Mark G. H. Scott, Zofia Varyova, Virginia Alvarez Garcia, Wayne Pearce, Katerina Stroud, Adrienne M. Flanagan, Gala Anastasia Electra Classen, I. Mohamed, Mohammad Amin Danesh, Djenat Belarbi
article en
2 citations

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 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.

Disease Models & MechanismsVol. 19(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), MRC Laboratory of Molecular Biology (GB), Iwate Medical University (JP), Université Paris Cité (FR), Wolfson Foundation (GB), Princess Anne Hospital (GB), Cambridge University Hospitals NHS Foundation Trust (GB), Royal National Orthopaedic Hospital (GB), Heriot-Watt University (GB), National Institute for Health and Care Research (GB), Sorbonne Paris Cité (FR), Délégation Paris 6 (FR), Institut Cochin (FR), CRUK Lung Cancer Centre of Excellence (GB), Exmouth Hospital (GB), University of Southampton (GB), University College London (GB), ESPCI Paris (FR)
Openalex Percentile: Top 14%
PI3K/AKT/mTOR signaling in cancer
1.61
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