Native American myopathy: Congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia

Stamm, Demetra S.; Aylsworth, Arthur S.; Stajich, Jeffrey M.; Kahler, Stephen G.; Thorne, Leigh B.; Speer, Marcy C.; Powell, Cynthia M.

doi:10.1002/ajmg.a.32370

Cited by 74 publications

(88 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Native American myopathy (NAM) is a rare inherited muscle disease that, at present, has only been reported in the Lumbee Native Americans of North Carolina [67]. The cardinal clinical features of the condition are mild muscle weakness, ptosis, myopathic facies, short stature, kyphoscoliosis, and a distinctive gait.…”

Section: Native American Myopathymentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

View full text Add to dashboard Cite

The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.

show abstract

Section: Native American Myopathymentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

View full text Add to dashboard Cite

show abstract

“…Furthermore, a hereditary triadopathy called Native American myopathy (NAM) is caused by a missense mutation of STAC3 (10). NAM, an autosomal-recessive disorder found within the Lumbee Native American population, is characterized by clinical features including congenital onset of muscle weakness, multiple joint contractures, dysmorphic facial features, and susceptibility to MH, with 36% of afflicted individuals dying by the age of 18 (14). Analysis of the analogous mutation in zebrafish stac3 showed that stac3 NAM leads to a partial loss of Ca 2+ release in muscle fibers (10), yet the mechanism for how Stac3 and Stac3 NAM modulate EC coupling has remained undefined.…”

mentioning

confidence: 99%

Congenital myopathy results from misregulation of a muscle Ca²⁺channel by mutant Stac3

Linsley

Hsu

Groom

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

View full text Add to dashboard Cite

Skeletal muscle contractions are initiated by an increase in Ca 2+ released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca 2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca 2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca 2+ in internal stores, which is consistent with increased SR luminal Ca 2+ . These findings define critical roles for Stac3 in EC coupling and human disease.zebrafish | skeletal muscle | excitation-contraction coupling | dihydropyridine receptor | Native American myopathy

show abstract

“…Thus, it seems that Stac3 is not required for junctional targeting but is essential for the EC coupling function of Ca V 1.1. Horstick et al (13) identified a missense mutation (W284S) of human Stac3 that causes a severe, recessively inherited myopathy, termed NAM (20). Additionally, they showed that EC coupling was diminished in fast-twitch muscle fibers expressing Stac3 NAM compared with WT Stac3.…”

mentioning

confidence: 99%

Stac3 has a direct role in skeletal muscle-type excitation–contraction coupling that is disrupted by a myopathy-causing mutation

Polster

Nelson

Olson³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In skeletal muscle, conformational coupling between Ca V 1.1 in the plasma membrane and type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR) is thought to underlie both excitation-contraction (EC) coupling Ca 2+ release from the SR and retrograde coupling by which RyR1 increases the magnitude of the Ca 2+ current via Ca V 1.1. Recent work has shown that EC coupling fails in muscle from mice and fish null for the protein Stac3 (SH3 and cysteine-rich domain 3) but did not establish the functional role of Stac3 in the Ca V 1.1-RyR1 interaction. We investigated this using both tsA201 cells and Stac3 KO myotubes. While confirming in tsA201 cells that Stac3 could support surface expression of Ca V 1.1 (coexpressed with its auxiliary β 1a and α 2 -δ 1 subunits) and the generation of large Ca 2+ currents, we found that without Stac3 the auxiliary γ 1 subunit also supported membrane expression of Ca V 1.1/β 1a /α 2 -δ 1 , but that this combination generated only tiny Ca 2+ currents. In Stac3 KO myotubes, there was reduced, but still substantial Ca V 1.1 in the plasma membrane. However, the Ca V 1.1 remaining in Stac3 KO myotubes did not generate appreciable Ca 2+ currents or EC coupling Ca 2+ release. Expression of WT Stac3 in Stac3 KO myotubes fully restored Ca 2+ currents and EC coupling Ca 2+ release, whereas expression of Stac3 W280S (containing the Native American myopathy mutation) partially restored Ca 2+ currents but only marginally restored EC coupling. We conclude that membrane trafficking of Ca V 1.1 is facilitated by, but does not require, Stac3, and that Stac3 is directly involved in conformational coupling between Ca V 1.1 and RyR1.L-type Ca 2+ channels | Stac3 protein | excitation-contraction coupling

show abstract

Native American myopathy: Congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia

Cited by 74 publications

References 20 publications

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Congenital myopathy results from misregulation of a muscle Ca²⁺channel by mutant Stac3

Stac3 has a direct role in skeletal muscle-type excitation–contraction coupling that is disrupted by a myopathy-causing mutation

Contact Info

Product

Resources

About

Native American myopathy: Congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia

Cited by 74 publications

References 20 publications

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Congenital myopathy results from misregulation of a muscle Ca2+channel by mutant Stac3

Stac3 has a direct role in skeletal muscle-type excitation–contraction coupling that is disrupted by a myopathy-causing mutation

Contact Info

Product

Resources

About

Congenital myopathy results from misregulation of a muscle Ca²⁺channel by mutant Stac3