Rare muscle disorder mutations reveal a precision medicine strategy

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by University of California - San Diego

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In healthy people, binding of the molecule acetylcholine to its receptor (center, purple) on skeletal muscle cells triggers muscle contraction underlying regular daily activities. Heritable mutations in the receptor can cause defects in muscle acetylcholine receptor signaling that results in congenital muscle weakness. The chemicals shown include known drugs and experimental molecules investigated in the current study to correct the receptor defects. Credit: Huanhuan Li, Hibbs Lab, UC San Diego.

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 a potential new use for an existing antidepressant.

The study, published in Nature, reveals for the first time the structural mechanisms underlying congenital myasthenic syndromes (CMS), a family of genetic disorders that weakens communication between nerves and muscles. The findings provide a roadmap for developing precision medicines tailored to the specific genetic mutation carried by each patient.

CMS affects children from birth or early childhood and can cause severe muscle weakness, difficulty walking, impaired breathing and, in the most severe cases, paralysis or death. Although physicians have long known that different mutations disrupt muscle signaling in different ways, exactly how those mutations alter the molecular machinery responsible for muscle contraction has remained a mystery.

The team used cryo-electron microscopy (cryo-EM), electrophysiology and chemical biology to investigate the human acetylcholine receptor, the protein that translates nerve signals into muscle contraction.

By determining 12 high-resolution structures of the disease-causing receptor variants, the researchers were able to see exactly how genetic mutations disrupt this essential communication between nerves and muscles.

(from left) Nature study first author Huanhuan Li, co-author Jinfeng Teng and senior author Ryan Hibbs. Credit: University Communications, UC San Diego

Two disease forms, two mechanisms

"We've known for decades which mutations cause these diseases, but not exactly how they damage the receptor or why certain drugs help some patients but not others," said senior author Ryan Hibbs, professor and chair of the Department of Neurobiology at UC San Diego's School of Biological Sciences.

"By visualizing these receptors at near-atomic resolution, we can now explain how the mutations disrupt their function and begin designing therapies that target the underlying molecular defect."

The team found that the two major forms of CMS arise through fundamentally different mechanisms.

In one form, called "fast-channel" CMS, mutations prevent the receptor from opening efficiently when the neurotransmitter acetylcholine binds. The researchers discovered a previously unknown drug-binding pocket that can partially restore receptor function using positive allosteric modulators—compounds that enhance receptor activity without directly activating it.

Importantly, different modulators worked better for different patient mutations, suggesting that future treatments could be personalized according to an individual's genetic diagnosis.

"Our results show that there probably won't be a single drug that works for every patient," Hibbs said. "Instead, different mutations respond differently, opening the door to precision medicine approaches for these disorders."

An antidepressant with new potential

The researchers also investigated "slow-channel" CMS, in which mutations cause receptors to remain open too long, damaging the neuromuscular junction over time. The study reveals exactly how two current treatments—quinidine and fluoxetine—block the defective receptors.

The team then investigated another promising therapeutic candidate: reboxetine, an antidepressant already approved in several countries. They found that reboxetine selectively suppresses the abnormal receptor activity responsible for slow-channel disease, making it a promising candidate for future clinical evaluation. Because reboxetine has already undergone extensive safety testing for depression, repurposing it for CMS could potentially accelerate the path toward new treatments.

A broader framework for mutations

Beyond identifying therapeutic opportunities, the work establishes general principles explaining how dozens of disease-causing mutations affect receptor function.

"Rather than studying one mutation at a time, we've uncovered the common mechanisms that explain two entire classes of congenital myasthenic syndromes," said first author Huanhuan Li, a postdoctoral researcher in Hibbs' laboratory. "That gives us a framework for understanding newly discovered patient mutations and for designing better therapies in the future."

The study also highlights the growing role of structural biology in precision medicine. The researchers combined cryo-EM—a technique in which biological samples are flash-frozen so quickly that molecules are captured in their native shapes—with functional measurements of receptor activity.

Together, these approaches allowed the team to directly observe how mutations alter protein structure and how candidate drugs restore normal function.

Much of the structural work was performed in UC San Diego's Goeddel Family Technology Sandbox, an advanced facility that provides researchers access to next-generation imaging technologies, including cryo-EM, to accelerate discoveries across the life sciences.

Along with Li and Hibbs, UC San Diego co-author Jinfeng Teng, a staff scientist in the Department of Neurobiology, performed key electrophysiological experiments that helped explain how candidate drugs rescue or inhibit mutant receptors.

Collaborators at Mayo Clinic contributed expertise in receptor physiology, while researchers at UC San Francisco synthesized the experimental compounds.

Publication details

Ryan Hibbs , Correcting congenital myasthenia-associated acetylcholine receptor defects, Nature (2026). DOI: 10.1038/s41586-026-10706-1. www.nature.com/articles/s41586-026-10706-1

Journal information: Nature

Clinical categories

NeurologyClinical pharmacologyClinical genetics Provided by University of California - San Diego Who's behind this story?

Sadie Harley

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