Researchers at The Research Institute of the Health Centre (The Institute) have played a leading role in identifying a new genetic cause of Charcot–Marie–Tooth disease, one of the most common inherited disorders affecting the peripheral nerves. The condition affects the nerves that control movement and sensation, often causing muscle weakness, difficulty walking and progressive disability.
In a study published in The Journal of Clinical Investigation, , Senior Scientist at The Institute, and her international collaborators found that mutations in a gene called ARHGAP19 are responsible for a previously unexplained inherited form of the disease. The team showed that these mutations reduce the protein’s normal activity, leading to damage in motor nerve cells that control muscle movement.
A gene with an important role in nerve cells
ARHGAP19 helps regulate proteins that act like on-off switches inside cells. These switches help control how cells maintain their internal shape and structure. Until now, ARHGAP19 had not been linked to inherited nerve disease.
By studying cells from affected individuals, the researchers found that the mutations reduce the amount or activity of the ARHGAP19 protein. This disrupts normal processes inside motor nerve cells, which are responsible for sending signals from the spinal cord to muscles. Over time, these changes damage the nerve fibers and weaken muscle control.
“This study shows that ARHGAP19 plays an essential role in maintaining healthy motor neurons,” says Prof. Lamarche-Vane. “When the gene does not function properly, the structural stability of these nerve cells is affected, which helps explain the progressive muscle weakness seen in patients.”
To understand how these mutations cause disease, the team combined patient-derived cell studies with animal models.
Motor nerve cells grown in the laboratory showed abnormal branching patterns. Similar movement problems and nerve defects were observed in fruit flies and zebrafish lacking the protein. These consistent findings across species show that ARHGAP19 is important for motor nerve development and function.
“When we first started, almost nothing was known about this gene,” says Xinyu Miao, PhD candidate in Prof. Lamarche-Vane’s lab. “It was exciting to bring together experts from different countries and disciplines and slowly build the story piece by piece. Seeing how our lab’s work fit into such a large international effort was incredibly rewarding.”
The project brought together trainees and research staff across institutions. In Prof. Lamarche-Vane’s lab, Yi He, PhD, contributed expertise in cellular functional assays, while Leif Leclaire, PhD candidate, participated in key protein purification and biochemical experiments together with Xinyu Miao.
Why this matters
Charcot–Marie–Tooth disease is genetically complex, and many patients still do not have a clear molecular diagnosis. Identifying ARHGAP19 as a new disease gene provides answers for affected families and strengthens understanding of how motor nerves are damaged.
The findings also point to a specific biological pathway that could eventually be targeted for development of new treatments.
The work from Prof. Lamarche-Vane’s laboratory was supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. The research also benefited from the expertise and equipment in The Institute’s .
About the paper
The study, “” was published in The Journal of Clinical Investigation (2025). The work was led by Natalia Dominik and Stephanie Efthymiou, with senior authors Mary M. Reilly, James E. C. Jepson, Nathalie Lamarche-Vane and Henry Houlden, and involved an international team of clinicians and scientists from Europe, North America, the Middle East and Australia. J Clin Invest. 2025;135(23):e184474. DOI: