Scientists at the University of California, San Diego have uncovered how genetic mutations cause a rare group of inherited neuromuscular disorders and identified promising new strategies to correct them, including potential new uses for existing antidepressants.
This study naturefor the first time revealed the structural mechanisms underlying congenital myasthenic syndromes (CMS), a family of genetic disorders that weaken communication between nerves and muscles. The findings provide a roadmap for developing precision medicine tailored to each patient’s specific genetic mutations.
CMS affects children from birth or early childhood and can cause severe muscle weakness, difficulty walking, breathing problems and, in the most severe cases, paralysis and death. Doctors have long known that different mutations disrupt muscle signaling in different ways, but how exactly those mutations alter the molecular mechanisms involved in muscle contraction has remained a mystery.
The research team used cryo-electron microscopy (cryo-EM), electrophysiology, and chemical biology to investigate human acetylcholine receptors, proteins that convert nerve signals into muscle contractions. By determining high-resolution structures of 12 disease-causing receptor variants, researchers were able to see exactly how genetic mutations disrupt this important communication between nerves and muscles.
Although we’ve known for decades which mutations cause these diseases, we didn’t know exactly how they damage the receptors or why certain drugs work for some patients and not others. By visualizing these receptors with near-atomic resolution, we can now explain how mutations disrupt their function and begin designing treatments that target the underlying molecular defects. ”
Ryan Hibbs, senior author, professor and chair, Department of Neurobiology, College of Biological Sciences, University of California, San Diego
The research team found that the two main forms of CMS occur through fundamentally different mechanisms.
In one form, called “fast channel” CMS, mutations prevent the receptor from opening efficiently when the neurotransmitter acetylcholine binds. Researchers have discovered a previously unknown drug-binding pocket in which positive allosteric modulators (compounds that activate receptors without directly activating them) can be used to partially restore receptor function.
Importantly, different modulators worked more effectively on mutations in different patients, suggesting that future treatments may be individualized according to an individual’s genetic diagnosis.
“Our results show that there is probably no single drug that will work for all patients,” Hibbs said. “Rather, different mutations respond differently, opening the door to precision medicine approaches to these diseases.”
The researchers also investigated “slow channel” CMS, where mutations cause receptors to remain open too long, damaging neuromuscular junctions over time. This study reveals exactly how two current treatments, quinidine and fluoxetine, block the defective receptors.
The team then investigated another promising treatment candidate, reboxetine. Reboxetine is an antidepressant that is already approved in several countries. They found that reboxetine selectively inhibits the aberrant receptor activity that causes slow channel disease, making it a promising candidate for future clinical evaluation. Reboxetine has already undergone extensive safety testing for depression, so repurposing it to CMS could accelerate the path to new treatments.
In addition to identifying therapeutic opportunities, this research establishes general principles that explain how the dozens of disease-causing mutations affect receptor function.
“Rather than studying one mutation at a time, we uncovered a common mechanism that explains two entire classes of congenital myasthenic syndromes,” said first author Huangfang Li, a postdoctoral fellow in the Hibbs lab. “This provides a framework for understanding newly discovered patient mutations and designing better treatments in the future.”
This study also highlights the growing role of structural biology in precision medicine. The researchers combined cryo-EM, a technique that rapidly freezes biological samples to capture molecules in their native form, with functional measurements of receptor activity. By combining these approaches, the team was able to directly observe how mutations change a protein’s structure and how drug candidates restore normal function.
Much of the structural work was done at the Goeddel Family Technology Sandbox at the University of California, San Diego. The sandbox is an advanced facility that allows researchers to access next-generation imaging technologies, such as cryo-EM, to accelerate discoveries across the life sciences.
Co-author Jingfeng Teng, a staff scientist in the Department of Neurobiology at the University of California, San Diego, along with Li and Hibbs, conducted important electrophysiological experiments that help explain how drug candidates rescue or inhibit mutant receptors. Collaborators at the Mayo Clinic provided expertise in receptor physiology, and researchers at the University of California, San Francisco synthesized the experimental compounds.
The study’s authors are Huanhuan Li, Nuriya Mukhtasimova, Jinfeng Teng, Elfie S. Cavalli, Xilin Gu, Jason K. Sello, Steven M. Sine, and Ryan E. Hibbs.
This research was supported by the National Institutes of Health (NS031744, NS120496, NS130831), the Myasthenia Gravis Foundation of America, and the American Heart Association (25POST1378255).
sauce:
University of California, San Diego
Reference magazines:
Lee, H. others. (2026). Corrects acetylcholine receptor deficiency associated with congenital myasthenia. nature. DOI: 10.1038/s41586-026-10706-1. https://www.nature.com/articles/s41586-026-10706-1
