STAC3 disorder: gene therapy and malignant hyperthermia

Skeletal muscle excitation-contraction (EC) coupling is a fundamental process in muscle physiology, in which an electrical signal, the action potential in the motor neuron, is converted into a mechanical response, muscle contraction. Protein complexes called voltage-gated calcium channels, consisting of the pore-forming CaV1.1 and additional CaV auxiliary subunits, mediate this signal transduction process by sensing the electrical signal and physically activating the opening of calcium release channels (ryanodine receptors; RyR1) in an intracellular compartment, the sarcoplasmic reticulum. The adaptor protein STAC3 is essential for this process and is the target for mutations causing STAC3 disorder, a rare recessively inherited congenital myopathy for which no cure or treatment is available. STAC3 disorder is characterized by severe muscle weakness and susceptibility to malignant hyperthermia (MH). MH is a condition characterized by a hypermetabolic response upon administration of volatile anesthetics and, if untreated, can be fatal. It typically associates with mutations in RyR1, suggesting that STAC3 is part of a larger complex. However, MH in STAC3 disorder displays some unconventional characteristics. In this research grant, we propose to explore the potential of STAC3 gene therapy to reverse the myopathy symptoms and investigate the molecular basis of malignant hyperthermia susceptibility. The results will not only provide the basis for establishing a gene therapy in humans, but also improve our understanding of not only the pathophysiology of MHS, but also of normal STAC3 function.