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DOI 10.1172/jci184474

Медицинская библиотека · The Journal of clinical investigation · 2025

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

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

СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПеревод в очереди

Аннотация

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.

Для цитирования: Dominik Natalia, Efthymiou Stephanie, Record Christopher J, Miao Xinyu, Lin Renee Q, Parmar Jevin M, Scardamaglia Annarita, Maroofian Reza, Lowe Simon A, Aughey Gabriel N, Wilson Abigail D, Curro Riccardo, Schnekenberg Ricardo P, Alavi Shahryar, Leclaire Leif, He Yi, Zhelcheska Kristina, Bellaïche Yohanns, Gaugué Isabelle, Skorupinska Mariola, Van de Vondel Liedewei, Da'as Sahar I, Turchetti Valentina, Güngör Serdal, Monahan Gavin V, Ghayoor Karimiani Ehsan, Jamshidi Yalda, Lamont Phillipa J, Armirola-Ricaurte Camila, Topaloglu Haluk, Jordanova Albena, Zaman Mashaya, Banu Selina H, Marques Wilson, Tomaselli Pedro J, Aynekin Busra, Cansu Ali, Per Huseyin, Güleç Ayten, Alvi Javeria Raza, Sultan Tipu, Khan Arif, Zifarelli Giovanni, Ibrahim Shahnaz, Mancini Grazia M S, Motazacker M M, Brusse Esther, Lupo Vincenzo, Sevilla Teresa, Başak A Nazli, Tekgul Seyma, Palvadeau Robin J, Baets Jonathan, Parman Yesim, Çakar Arman, Horvath Rita, Haack Tobias B, Stahl Jan-Hendrik, Grundmann-Hauser Kathrin, Park Joohyun, Zuchner Stephan, Laing Nigel G, Wilson Lindsay A, Rossor Alexander M, Polke James, Figueiredo Fernanda Barbosa, Pessoa André, Kok Fernando, Coimbra-Neto Antônio Rodrigues, Franca Marcondes C, Ravenscroft Gianina, Hamed Sherifa A, Chung Wendy K, Pittman Alan M, Osborn Daniel P, Hanna Michael, Cortese Andrea, Reilly Mary M, Jepson James Ec, Lamarche-Vane Nathalie, Houlden Henry. Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.. The Journal of clinical investigation. 2025. DOI: 10.1172/jci184474.

Предметные рубрики MeSH

HumansAnimalsGTPase-Activating ProteinsZebrafishCharcot-Marie-Tooth DiseaseDrosophila melanogasterFemaleMaleAllelesMotor NeuronsLoss of Function MutationZebrafish ProteinsrhoA GTP-Binding Protein
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