Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy

Nat Commun. 2013;4:1952. doi: 10.1038/ncomms2952.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Cleft Palate / genetics*
  • Cleft Palate / physiopathology*
  • Embryo, Nonmammalian / metabolism
  • Excitation Contraction Coupling*
  • Humans
  • Malignant Hyperthermia / genetics*
  • Malignant Hyperthermia / physiopathology*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Myofibrils / metabolism
  • Myofibrils / ultrastructure
  • Myotonia Congenita / genetics*
  • Myotonia Congenita / pathology
  • Myotonia Congenita / physiopathology*
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Organ Specificity / genetics
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Swimming
  • Touch
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / chemistry
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Ryanodine Receptor Calcium Release Channel
  • Stac3 protein, human
  • Stac3 protein, zebrafish
  • Zebrafish Proteins

Supplementary concepts

  • Native American myopathy