Scientists have uncovered the mutation that causes Native American myopathy (NAM), an inherited muscular disease prevalent in the Southern regions of the United States. The discovery could lead to potential therapies for the rare disease and answer broader questions about human musclar diseases. The findings were published today in Nature Communications.

Cleft palate, drooping facial features, and short stature are just some features of NAM, a muscular disease that strikes one in 5,000 Lumbee Indians from North Carolina. NAM, like most myopathies, is the result of muscle fibers being out of whack and failing to properly contract.

Individuals with NAM are also susceptible to malignant hyperthermia, a life-threatening condition marked by excessive overheating and accelerated heart rate. It is triggered by exposure to anesthetic drugs and can lead to serious complications during a surgery if a doctor is unaware that a patient has NAM.

The new investigation didn't begins in humans; rather the mutation was stumbled upon in zebrafish. Zebrafish are popular with scientists who are exploring how muscles work. The genome of zebrafish has been sequenced and is easy to manipulate when searching for novel mutations. Young zebrafish also have translucent skin and scales, making it easy to visually study their muscle architecture.

While searching for zebrafish genes involved in skeletal muscle contractions, the researchers isolated a group of young fish whose tails wouldn't properly coil and had problems swimming. They discovered the fish had a mutation in Stac3, a gene previously linked to muscle development, but had no known connection to regular mucle function.

Further analysis showed that Stac3 is required for translating signals from the zebrafish brain into muscle contractions, a process known as excitation-contraction coupling.

Given the myopathic features of the mutant fish, the team investigated whether or not the Stac3 gene is implicated in any human muscle disorders.

Prior studies linked NAM to a defined segment of the human genome, but didn't isolate which gene out of the hundreds in the region might be responsible for the disease.

The researchers found that Stac3 mapped to this gene region in humans, and five different Lumbee Indian families with a history of NAM were recruited to see if afflicted members had any mutations in the Stac3 gene.

Humans carry two copies of every gene, and NAM is a recessive genetic disease, meaning its disease-causing mutation must be present in both copies of any suspected gene. If one copy is mutated, the person won't have NAM, but if he or she marries a person with similar genetics, their kids will have a higher risk of developing the disease.

All of the individuals with NAM carried the exact same mutation in both copies of their Stac3 genes, while their parents had a mutation in one copy of their Stac3 gene. This led the authors to conclude that this mutation in Stac3 is the cause of NAM.

Stac3-mutant zebrafish now offer an experimental realm for identifying drugs that might reverse the muscular defect in humans.

Source: Horstick EJ, Linsley JW, Dowling JJ, et al. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nature Communications. 2013.