Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy.
Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca(2+) from internal stores to initiate muscle contraction. Defects in excitation-contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation-contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca(2+) imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation-contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling. These findings enhance our understanding of both excitation-contraction coupling and the pathology of myopathies.
Horstick, EJ; Linsley, JW; Dowling, JJ; Hauser, MA; McDonald, KK; Ashley-Koch, A; Saint-Amant, L; Satish, A; Cui, WW; Zhou, W; Sprague, SM; Stamm, DS; Powell, CM; Speer, MC; Franzini-Armstrong, C; Hirata, H; Kuwada, JY
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