Biallelic variants inARHGAP19cause a motor-predominant neuropathy with asymmetry and conduction slowing
Author:
Dominik NataliaORCID, Efthymiou StephanieORCID, Record Christopher J.ORCID, Miao Xinyu, Lin Renee, Parmar JevinORCID, Scardamaglia Annarita, Maroofian RezaORCID, Aughey GabrielORCID, Wilson Abigail, Lowe Simon, Curro Riccardo, Schnekenberg Ricardo P., Alavi ShahryarORCID, Leclaire Leif, He Yi, Zhelchenska Kristina, Bellaiche Yohanns, Gaugué Isabelle, Skorupinska Mariola, Van de Vondel LiedeweiORCID, Da’as Sahar I.ORCID, Turchetti Valentina, Güngör Serdal, Karimiani Ehsan Ghayoor, Ricaurte Camila Armirola, Topaloglu Haluk, Jordanova AlbenaORCID, Zaman Mashaya, Banu Selina H., Marques Wilson, Tomaselli Pedro JoséORCID, 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. Mahdi, Brusse Esther, Lupo Vincenzo, Sevilla TeresaORCID, Başak A Nazlı, Tekgul Seyma, Palvadeau Robin, Baets JonathanORCID, Parman Yesim, Çakar Arman, Horvath Rita, Haack Tobias B.ORCID, Stahl Jan-Hendrik, Grundmann-Hauser Kathrin, Park JoohyunORCID, Züchner Stephan, Laing Nigel G., Wilson Lindsay, Rossor Alexander M., Polke James, Figueiredo Fernanda Barbosa, Pessoa André Luiz, Kok Fernando, Coimbra-Neto Antônio RodriguesORCID, França Marcondes C., Jamshidi Yalda, Ravenscroft Gianina, Hamed Sherifa Ahmed, Chung Wendy K., Osborn Daniel P.ORCID, Hanna Michael, Cortese Andrea, Reilly Mary M., Jepson James E. C., Lamarche-Vane Nathalie, Houlden HenryORCID
Abstract
AbstractCharcot-Marie-Tooth Disease is a clinically and genetically heterogeneous group of hereditary neuropathies, with over 100 causative genes identified to date. Despite progress in genetic sequencing, around a quarter of patients remain unsolved. Through international collaborations, we identified 16 recessive variants in Rho GTPase activating protein 19 (ARHGAP19) causing motor-predominant neuropathy with conduction slowing in 25 individuals from 20 unrelated multi-ancestry families. ARHGAP19 is a GTPase-activating protein with activity towards RhoA.In vitrobiochemical assays revealed that variants located within the GAP domain cause loss of GAP activity. iPSc-derived motor neurons exhibited 50% knockdown of ARHGAP19 protein.In vivogenetic perturbations of theDrosophila melanogaster ARHGAP19orthologRhoGAP54Dreduced self-driven locomotor activity and startle responses to visual stimuli. Zebrafish loss-of-function models similarly exhibited movement deficits, coupled with increased motor neuron axonal branching but shorter caudal primary motor neurons. Together, these findings establishARHGAP19as a novel cause of early-onset neuropathy through a loss-of-function mechanism.
Publisher
Cold Spring Harbor Laboratory
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