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

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, for around a quarter of patients the disease has lacked a genetic explanation. Here, we identified 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. Through the use of patient lines, in vitro GAP assays and in silico molecular modeling, we provided evidence that CMT-associated ARHGAP19 variants act through a loss-of-function (LOF) mechanism. LOF in ARHGAP19 orthologues in Drosophila melanogaster and Danio rerio induced motor defects in axonal and synaptic morphology. Similar cellular phenotypes were observed in ARHGAP19 patient-derived motoneurons. Transcriptomic studies further demonstrated 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 LOF mechanism.

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Journal
Journal of Clinical Investigation
Published
2025-10-14
DOI
https://doi.org/10.1172/jci184474
Primary Topic
Neurological diseases and metabolism
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article
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article

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

Arman Çakar, Alexander Martin Rossor, Gabriel Aughey, Antônio Rodrigues Coimbra Neto et al.
Journal of Clinical Investigation
Neurological diseases and metabolism
article

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

Arman Çakar, Alexander Martin Rossor, Gabriel Aughey, Antônio Rodrigues Coimbra Neto, Simon A. Lowe, Andrea Cortese, Grazia M.S. Mancini, Isabelle Gaugué, Michael G. Hanna, M. Mahdi Motazacker, Teresa Sevilla, Marcondes C. França, Robin Palvadeau, Riccardo Curró, Tobias B. Haack, Christopher J. Record, Annarita Scardamaglia, Camila Armirola-Ricaurte, G. Monahan, Wendy K. Chung, Mary M. Reilly, Alan Pittman, Serdal Güngör, Şeyma Tekgül, Ayten Güleç, Mariola Skorupinska, Stéphanie Efthymiou, Valentina Turchetti, Sherifa A. Hamed, Sahar Isa Da'as, Daniel P. S. Osborn, Nigel G. Laing, Shahnaz Ibrahim, Rita Horváth, Natalia Dominik, Wilson Marques, Esther Brusse, Vincenzo Lupo, Kristina Zhelcheska, Fernanda Barbosa Figueiredo, Kathrin Grundmann‐Hauser, Ricardo Parolin Schnekenberg, Yohanns Bellaı̈che, Pedro José Tomaselli, Javeria Raza Alvi, Hüseyin Per, Fernando Kok, Ali Cansu, Yalda Jamshidi, Mashaya Zaman, Giovanni Zifarelli, Albena Jordanova, Abigail D. Wilson, Gianina Ravenscroft, André Luiz Santos Pessoa, Jonathan Baets, Nathalie Lamarche‐Vane, James E.C. Jepson, Selina Banu, Henry Houlden, Büşra Aynekin, Lindsay A. Wilson, Shahryar Alavi, J. Parmar, Haluk Topaloğlu, Leif Leclaire, Joohyun Park, Tipu Sultan, Xinyu Miao, Ehsan Ghayoor Karimiani, Liedewei Van de Vondel, James Polke, Arif O. Khan, A. Nazli Başak, Phillipa J. Lamont, Yi He, Reneé C. Lin, Stephan Züchner, J. Stahl, Reza Maroofian, Yeşim Parman
article en

Abstract

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, for around a quarter of patients the disease has lacked a genetic explanation. Here, we identified 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. Through the use of patient lines, in vitro GAP assays and in silico molecular modeling, we provided evidence that CMT-associated ARHGAP19 variants act through a loss-of-function (LOF) mechanism. LOF in ARHGAP19 orthologues in Drosophila melanogaster and Danio rerio induced motor defects in axonal and synaptic morphology. Similar cellular phenotypes were observed in ARHGAP19 patient-derived motoneurons. Transcriptomic studies further demonstrated 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 LOF mechanism.

Journal of Clinical InvestigationVol. 135(23)
Aga Khan University (PK), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Koç University (TR), Harvard University (US), University of Miami (US), University of Antwerp (BE), Inserm (FR), Universitat de València (ES), Karadeniz Technical University (TR), St George's, University of London (GB), The University of Western Australia (AU), Universidade de São Paulo (BR), Universidade Estadual de Campinas (UNICAMP) (BR), Université Sorbonne Nouvelle (FR), Inonu University (TR), University of Cambridge (GB), University of Pavia (IT), Université Paris Sciences et Lettres (FR), Royal Perth Hospital (AU), Harry Perkins Institute of Medical Research (AU), Bangladesh Shishu (Children) Hospital & Institute (BD), McGill University Health Centre (CA), Erasmus MC (NL), Dubai Hospital (AE), Medical University of Sofia (BG), Hospital Universitari i Politècnic La Fe (ES), Epilepsy Research UK (GB), Sorbonne Université (FR), Cambridge School (PT), Centro Universitário UNINOVAFAPI (BR), Antwerp University Hospital (BE), Biruni University (TR), Centre for Biomedical Network Research on Rare Diseases (ES), Centro de Investigación Biomédica en Red (ES), Dr. John T. Macdonald Foundation (US), VIB-UAntwerp Center for Molecular Neurology (BE), Centogene (Germany) (DE), Mendelics (BR), Hospital Infantil Albert Sabin (BR), Hertie Institute for Clinical Brain Research (DE), National Hospital for Neurology and Neurosurgery (GB), Epilepsy Foundation (AU), Clinics Hospital of Ribeirão Preto (BR), Institute of Structural and Molecular Biology (GB), Centro de Investigacion Principe Felipe (ES), Instituto de Investigación Sanitaria La Fe (ES), Genomic (Brazil) (BR), Génétique et biologie du développement (FR), University College London (GB), McGill University (CA), Université Paris 1 Panthéon-Sorbonne (FR), Hacettepe University (TR), Istanbul University (TR), Institut Curie (FR), University of Tübingen (DE), Erciyes University (TR), University of Amsterdam (NL), Assiut University (EG)
Wellcome Trust, National Institute for Health and Care Research, University College London, Università degli Studi dell'Aquila, Medical Research Council
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Neurological diseases and metabolism
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