Dominik, N;
Efthymiou, S;
Record, CJ;
Miao, X;
Lin, RQ;
Parmar, JM;
Scardamaglia, A;
... Houlden, H; + view all
(2026)
Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy.
Journal of Clinical Investigation
, 136
(3)
, Article e191370. 10.1172/JCI191370.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI191370 |
| Publisher version: | https://doi.org/10.1172/jci191370 |
| Language: | English |
| Additional information: | Copyright: © 2025, Dominik et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. |
| Keywords: | Cancer, Cell biology, Oncology, Signal transduction, GATA6 Transcription Factor, Pancreatic Neoplasms, Humans, Proto-Oncogene Proteins p21(ras), MAP Kinase Signaling System, Cell Line, Tumor, Transcription Factors, Gene Expression Regulation, Neoplastic, Animals, Mice, Extracellular Signal-Regulated MAP Kinases, Cell Differentiation, Neoplasm Proteins |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10221254 |
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