Biallelic variants in ARHGAP19 cause a motor-predominant neuropathy with asymmetry and conduction slowing
Dominik, N.; Efthymiou, S.; Record, C. J.; Miao, X.; Lin, R.; Parmar, J.; Scardamaglia, A.; Maroofian, R.; Aughey, G.; Wilson, A.; Lowe, S.; Curro, R.; Schnekenberg, R. P.; Alavi, S.; Leclaire, L.; He, Y.; Zhelchenska, K.; Bellaiche, Y.; Gaugue, I.; Skorupinska, M.; Van de Vondel, L.; Da'as, S.; Turchetti, V.; Gungor, S.; Karimiani, E. G.; Armirola Ricaurte, C.; Topaloglu, H.; Jordanova, A.; Zaman, M.; Banu, S. H.; Marques, W.; Tomaselli, P. J.; Aynekin, B.; Cansu, A.; Per, H.; Gulec, A.; Alvi, J. R.; Sultan, T.; Khan, A.; Zifarelli, G.; Ibrahim, S.; Mancini, G. M. S.; Motazacker, M. M.; Bruss
Show abstract
Charcot-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 vitro biochemical 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 vivo genetic perturbations of the Drosophila melanogaster ARHGAP19 ortholog RhoGAP54D reduced 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 establish ARHGAP19 as a novel cause of early-onset neuropathy through a loss-of-function mechanism.
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