Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy

Natalia Dominik; Stephanie Efthymiou; Christopher J Record; Xinyu Miao; Renee Q Lin; Jevin M Parmar; Annarita Scardamaglia; Reza Maroofian; Simon A Lowe; Gabriel N Aughey; Abigail D Wilson; Riccardo Curro; Ricardo P Schnekenberg; Shahryar Alavi; Leif Leclaire; Yi He; Kristina Zhelcheska; Yohanns Bellaiche; Isabelle Gaugué; Mariola Skorupinska; Liedewei Van de Vondel; Sahar I Da'as; Valentina Turchetti; Serdal Güngör; Gavin V Monahan; Ehsan Ghayoor Karimiani; Yalda Jamshidi; Phillipa J Lamont; Camila Armirola-Ricaurte; Haluk Topaloglu; Albena Jordanova; Mashaya Zaman; Selina H Banu; Wilson Marques; Pedro J Tomaselli; Busra Aynekin; Ali Cansu; Huseyin Per; Ayten Güleç; Javeria Raza Alvi; Tipu Sultan; Arif Khan; Giovanni Zifarelli; Shahnaz Ibrahim; Grazia M S Mancini; M M Motazacker; Esther Brusse; Vincenzo Lupo; Teresa Sevilla; A Nazli Başak; Seyma Tekgul; Robin J Palvadeau; Jonathan Baets; Yesim Parman; Arman Çakar; Rita Horvath; Tobias B Haack; Jan-Hendrik Stahl; Kathrin Grundmann-Hauser; Joohyun Park; Stephan Zuchner; Nigel G Laing; Lindsay A Wilson; Alexander M Rossor; James Polke; Fernanda Barbosa Figueiredo; André Pessoa; Fernando Kok; Antônio Rodrigues Coimbra-Neto; Marcondes C Franca, Jr; Gianina Ravenscroft; Sherifa A Hamed; Wendy K Chung; Alan M Pittman; Daniel P Osborn; Michael Hanna; Andrea Cortese; Mary M Reilly; James Ec Jepson; Nathalie Lamarche-Vane; Henry Houlden

doi:10.1172/JCI184474

Back

Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy

Journal article

Peer reviewed

Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy

Natalia Dominik, Stephanie Efthymiou, Christopher J Record, Xinyu Miao, Renee Q Lin, Jevin M Parmar, Annarita Scardamaglia, Reza Maroofian, Simon A Lowe, Gabriel N Aughey, …

The Journal of clinical investigation

2025-10-14

DOI: https://doi.org/10.1172/JCI184474

PMID: 41086021

Appears in Miller School of Medicine - Latest Publications

Abstract

Neuromuscular disease

Genetics

Neuroscience

Charcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Here, we identify 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Combined in vitro and in vivo studies reveal that human ARHGAP19, and conserved ARHGAP19 orthologs in Drosophila and Zebrafish, influence motoneuron morphology and promote locomotor capacity. Transcriptomic studies further demonstrate that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a loss-of-function mechanism.

Files and links (1)

url

https://doi.org/10.1172/JCI184474View

Published (Version of record) Open

Metrics

1 Record Views

See more details

Details

Title: Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy
Creators: Natalia Dominik - University College London
Stephanie Efthymiou - University College London
Christopher J Record - National Hospital for Neurology and Neurosurgery
Xinyu Miao - McGill University
Renee Q Lin - UCL Queen Square Institute of Neurology
Jevin M Parmar - Harry Perkins Institute of Medical Research
Annarita Scardamaglia - University College London
Reza Maroofian - University College London
Simon A Lowe - University College London
Gabriel N Aughey - University College London
Abigail D Wilson - National Hospital for Neurology and Neurosurgery
Riccardo Curro - National Hospital for Neurology and Neurosurgery
Ricardo P Schnekenberg - National Hospital for Neurology and Neurosurgery
Shahryar Alavi - National Hospital for Neurology and Neurosurgery
Leif Leclaire - McGill University
Yi He - McGill University
Kristina Zhelcheska - National Hospital for Neurology and Neurosurgery
Yohanns Bellaiche - Sorbonne Université
Isabelle Gaugué - Sorbonne Université
Mariola Skorupinska - National Hospital for Neurology and Neurosurgery
Liedewei Van de Vondel - University of Antwerp
Sahar I Da'as - Department of Human Genetics, Sidra Medicine, Doha, Qatar
Valentina Turchetti - University College London
Serdal Güngör - Inonu University
Gavin V Monahan - Harry Perkins Institute of Medical Research
Ehsan Ghayoor Karimiani - UCL Queen Square Institute of Neurology
Yalda Jamshidi - University of London
Phillipa J Lamont - Harry Perkins Institute of Medical Research
Camila Armirola-Ricaurte - VIB-UAntwerp Center for Molecular Neurology
Haluk Topaloglu - Hacettepe University
Albena Jordanova - VIB-UAntwerp Center for Molecular Neurology
Mashaya Zaman - Dhaka Shishu Hospital
Selina H Banu - Dhaka Shishu Hospital
Wilson Marques - Universidade de São Paulo
Pedro J Tomaselli - Universidade de São Paulo
Busra Aynekin - National Hospital for Neurology and Neurosurgery
Ali Cansu - Karadeniz Technical University
Huseyin Per - Erciyes University
Ayten Güleç - Erciyes University
Javeria Raza Alvi - Children's Hospital & the Institute of Child Health, Lahore, Pakistan
Tipu Sultan - Children's Hospital & the Institute of Child Health, Lahore, Pakistan
Arif Khan - Dubai Hospital
Giovanni Zifarelli - Centogene
Shahnaz Ibrahim - Aga Khan University
Grazia M S Mancini - Erasmus MC
M M Motazacker - University of Amsterdam
Esther Brusse - Erasmus MC
Vincenzo Lupo - Centro de Investigacion Principe Felipe
Teresa Sevilla - Instituto de Investigación Sanitaria La Fe
A Nazli Başak - Koç University
Seyma Tekgul - Koç University
Robin J Palvadeau - Koç University
Jonathan Baets - University of Antwerp
Yesim Parman - Istanbul University
Arman Çakar - Istanbul University
Rita Horvath - University of Cambridge
Tobias B Haack - University of Tübingen
Jan-Hendrik Stahl - University of Tübingen
Kathrin Grundmann-Hauser - University of Tübingen
Joohyun Park - University of Tübingen
Stephan Zuchner - Dr. John T. Macdonald Foundation
Nigel G Laing - Harry Perkins Institute of Medical Research
Lindsay A Wilson - National Hospital for Neurology and Neurosurgery
Alexander M Rossor - National Hospital for Neurology and Neurosurgery
James Polke - National Hospital for Neurology and Neurosurgery
Fernanda Barbosa Figueiredo - Genomic
André Pessoa - Hospital Infantil Albert Sabin
Fernando Kok - Genomic
Antônio Rodrigues Coimbra-Neto - Universidade Estadual de Campinas (UNICAMP)
Marcondes C Franca, Jr - Universidade Estadual de Campinas (UNICAMP)
Gianina Ravenscroft - The University of Western Australia
Sherifa A Hamed - Assiut University
Wendy K Chung - Harvard University
Alan M Pittman - University of London
Daniel P Osborn - University of London
Michael Hanna - National Hospital for Neurology and Neurosurgery
Andrea Cortese - UCL Australia
Mary M Reilly - National Hospital for Neurology and Neurosurgery
James Ec Jepson - National Hospital for Neurology and Neurosurgery
Nathalie Lamarche-Vane - McGill University
Henry Houlden - National Hospital for Neurology and Neurosurgery
Publication Details: The Journal of clinical investigation
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 41086021
Record Identifier: 991032830838802976