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

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

doi:10.1242/dmm.052527

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

Priyanka Tibarewal (Lead / Corresponding author)
, Victoria Rathbone
, Sarah E. Conduit
, Gala Anastasia Electra Classen
, Fiona Black
, Mohammad Amin Danesh
, Georgia Constantinou
, Zeinab Asgarian
, Koujiro Tohyama
, Nisha Kriplani
, Virginia Alvarez Garcia
, Elizabeth Foxall
, Djenat Belarbi
, Marie Leverve
, Wayne Pearce
, Mahreen Adil
, Zofia Varyova
, Lucia Conde
, Adriana Alves
, Glenn R. Masson

Roger L. Williams, Adrienne M. Flanagan, Javier Herrero, Isra Ahmed Mohamed, Katerina Stroud, Marc Tischkowitz, Katherine Lachlan, Cheryl L. Scudamore, Mark G.H. Scott, Nicholas R. Leslie, Nicoletta Kessaris (Lead / Corresponding author), Bart Vanhaesebroeck (Lead / Corresponding author)

MED Cancer Research

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	dmm052527
Number of pages	20
Journal	DMM Disease Models and Mechanisms
Volume	19
Issue number	1
DOIs	https://doi.org/10.1242/dmm.052527
Publication status	Published - 1 Jan 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ASD
Cancer
Macrocephaly
PHTS
PI3K
PTEN

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Medicine (miscellaneous)
Immunology and Microbiology (miscellaneous)
General Biochemistry,Genetics and Molecular Biology

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10.1242/dmm.052527Licence: CC BY

Final Published VersionFinal published version, 9.2 MBLicence: CC BY

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Tibarewal, P., Rathbone, V., Conduit, S. E., Classen, G. A. E., Black, F., Danesh, M. A., Constantinou, G., Asgarian, Z., Tohyama, K., Kriplani, N., Garcia, V. A., Foxall, E., Belarbi, D., Leverve, M., Pearce, W., Adil, M., Varyova, Z., Conde, L., Alves, A., ... Vanhaesebroeck, B. (2026). Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN hamartoma tumour syndrome. DMM Disease Models and Mechanisms, 19(1), Article dmm052527. https://doi.org/10.1242/dmm.052527

@article{906398fce8344251aa2d11f0c50592fa,

title = "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{\textquoteright}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.",

keywords = "ASD, Cancer, Macrocephaly, PHTS, PI3K, PTEN",

author = "Priyanka Tibarewal and Victoria Rathbone and Conduit, \{Sarah E.\} and Classen, \{Gala Anastasia Electra\} and Fiona Black and Danesh, \{Mohammad Amin\} and Georgia Constantinou and Zeinab Asgarian and Koujiro Tohyama and Nisha Kriplani and Garcia, \{Virginia Alvarez\} and Elizabeth Foxall and Djenat Belarbi and Marie Leverve and Wayne Pearce and Mahreen Adil and Zofia Varyova and Lucia Conde and Adriana Alves and Masson, \{Glenn R.\} and Williams, \{Roger L.\} and Flanagan, \{Adrienne M.\} and Javier Herrero and Mohamed, \{Isra Ahmed\} and Katerina Stroud and Marc Tischkowitz and Katherine Lachlan and Scudamore, \{Cheryl L.\} and Scott, \{Mark G.H.\} and Leslie, \{Nicholas R.\} and Nicoletta Kessaris and Bart Vanhaesebroeck",

note = "Publisher Copyright: {\textcopyright} 2026. Published by The Company of Biologists.",

year = "2026",

month = jan,

day = "1",

doi = "10.1242/dmm.052527",

language = "English",

volume = "19",

journal = "DMM Disease Models and Mechanisms",

issn = "1754-8403",

publisher = "Company of Biologists Ltd",

number = "1",

}

Tibarewal, P, Rathbone, V, Conduit, SE, Classen, GAE, Black, F, Danesh, MA, Constantinou, G, Asgarian, Z, Tohyama, K, Kriplani, N, Garcia, VA, Foxall, E, Belarbi, D, Leverve, M, Pearce, W, Adil, M, Varyova, Z, Conde, L, Alves, A, Masson, GR, Williams, RL, Flanagan, AM, Herrero, J, Mohamed, IA, Stroud, K, Tischkowitz, M, Lachlan, K, Scudamore, CL, Scott, MGH, Leslie, NR, Kessaris, N & Vanhaesebroeck, B 2026, 'Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN hamartoma tumour syndrome', DMM Disease Models and Mechanisms, vol. 19, no. 1, dmm052527. https://doi.org/10.1242/dmm.052527

TY - JOUR

T1 - Impaired nuclear PTEN function drives macrocephaly, lymphadenopathy and late-onset cancer in PTEN hamartoma tumour syndrome

AU - Tibarewal, Priyanka

AU - Rathbone, Victoria

AU - Conduit, Sarah E.

AU - Classen, Gala Anastasia Electra

AU - Black, Fiona

AU - Danesh, Mohammad Amin

AU - Constantinou, Georgia

AU - Asgarian, Zeinab

AU - Tohyama, Koujiro

AU - Kriplani, Nisha

AU - Garcia, Virginia Alvarez

AU - Foxall, Elizabeth

AU - Belarbi, Djenat

AU - Leverve, Marie

AU - Pearce, Wayne

AU - Adil, Mahreen

AU - Varyova, Zofia

AU - Conde, Lucia

AU - Alves, Adriana

AU - Masson, Glenn R.

AU - Williams, Roger L.

AU - Flanagan, Adrienne M.

AU - Herrero, Javier

AU - Mohamed, Isra Ahmed

AU - Stroud, Katerina

AU - Tischkowitz, Marc

AU - Lachlan, Katherine

AU - Scudamore, Cheryl L.

AU - Scott, Mark G.H.

AU - Leslie, Nicholas R.

AU - Kessaris, Nicoletta

AU - Vanhaesebroeck, Bart

PY - 2026/1/1

Y1 - 2026/1/1

N2 - 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.

AB - 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.

KW - ASD

KW - Cancer

KW - Macrocephaly

KW - PHTS

KW - PI3K

KW - PTEN

UR - https://www.scopus.com/pages/publications/105026873213

U2 - 10.1242/dmm.052527

DO - 10.1242/dmm.052527

M3 - Article

C2 - 41215730

AN - SCOPUS:105026873213

SN - 1754-8403

VL - 19

JO - DMM Disease Models and Mechanisms

JF - DMM Disease Models and Mechanisms

IS - 1

M1 - dmm052527

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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