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,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
{"title":"Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.","authors":"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,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","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Clinical Investigation","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1172/jci184474","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract
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.
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