Biallelic variants in ARHGAP19 cause a motor-predominant neuropathy with asymmetry and conduction slowing

Natalia Dominik; Stéphanie Efthymiou; Christopher J. Record; Xinyu Miao; Renee Lin; J. Parmar; Annarita Scardamaglia; Reza Maroofian; Gabriel Aughey; Abigail D. Wilson; Simon A. Lowe; Riccardo Curró; Ricardo Parolin Schnekenberg; Shahryar Alavi; Leif Leclaire; Yi He; Kristina Zhelchenska; Yohanns Bellaı̈che; Isabelle Gaugué; Mariola Skorupinska; Liedewei Van de Vondel; Sahar Isa Da'as; Valentina Turchetti; Serdal Güngör; Ehsan Ghayoor Karimiani; Camila Armirola-Ricaurte; Haluk Topaloğlu; Albena Jordanova; Mashaya Zaman; Selina Husna Banu

doi:10.1101/2024.05.10.24306768

Genetic & Genomic MedicinemedRxivMay 10, 2024

Preprint

Biallelic variants in ARHGAP19 cause a motor-predominant neuropathy with asymmetry and conduction slowing

Natalia Dominik iD, Stéphanie Efthymiou iD, Christopher J. Record iD, Xinyu Miao, Renee Lin, J. Parmar iD, Annarita Scardamaglia iD, Reza Maroofian iD, Gabriel Aughey iD, Abigail D. Wilson iD, Simon A. Lowe iD, Riccardo Curró iD, Ricardo Parolin Schnekenberg iD, Shahryar Alavi iD, Leif Leclaire, Yi He iD, Kristina Zhelchenska, Yohanns Bellaı̈che iD, Isabelle Gaugué iD, Mariola Skorupinska iD, Liedewei Van de Vondel iD, Sahar Isa Da'as iD, Valentina Turchetti, Serdal Güngör iD, Ehsan Ghayoor Karimiani iD, , Henry Houlden iD

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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