Key result
The NAM mutation and loss of Stac3 decrease the amount, organization, stability, and voltage sensitivity of Ca2+ channels in muscles, linking STAC3 to congenital myopathy and malignant hyperthermia.
Stac3 controls excitation-contraction coupling by regulating Ca2+ channels in skeletal muscle, and its mutations are linked to Native American myopathy and malignant hyperthermia.
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STAC3 variants merit inclusion in myopathy/MH genetic panels; leaves open therapeutic targeting of Ca2+ channel stability.
Significance Skeletal muscle contractions are regulated by a process called excitation–contraction (EC) coupling, and defects in it are associated with numerous human myopathies. Recently, stac3 (SH3 and cysteine-rich domain 3) was identified as a key regulator of EC coupling and a STAC3 mutation as causal for the debilitating Native American myopathy (NAM). We now show that Stac3 controls EC coupling by regulating Ca 2+ channels in muscles. Both the NAM mutation and a mutation that leads to the loss of Stac3 decrease the amount, organization, stability, and voltage sensitivity of Ca 2+ channels. Furthermore, we find evidence that the NAM allele of STAC3 is linked to malignant hyperthermia, a common pharmacogenic disorder. These findings define critical roles for Stac3 in muscle contraction and human disease.
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Linsley et al. (2016) studied Native American myopathy (NAM) and malignant hyperthermia. STAC3 mutation (NAM mutation) was evaluated on Ca2+ channel amount, organization, stability, and voltage sensitivity. The NAM mutation and loss of Stac3 decrease the amount, organization, stability, and voltage sensitivity of Ca2+ channels in muscles, linking STAC3 to congenital myopathy and malignant hyperthermia.
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