A research group has identified specific mutations in a gene on chromosome 15 called KBTBD13 that cause a type of nemaline myopathy (NM), a disease in which thread- or rod-like ("nemaline") material forms clumps in affected muscle.
The newly identified mutations cause type 6 NM. A number of mutations in genes associated with other subtypes of the disease already have been identified.
NM is a congenital myopathy, meaning it is present at birth due to hereditary or environmental factors, and disease onset typically occurs in infancy or childhood, but can manifest in adulthood as well. NM types are classified according to age at disease onset and severity of symptoms. The disease causes weakness and poor tone in the muscles of the face, neck and upper limbs, and often affects the respiratory muscles.
One additional symptom, "slowness" of movement, is exclusive to type 6 NM, and not found in other congenital myopathies.
The identification of mutations in the KBTBD13 gene as the genetic cause of type 6 NM may help inform scientists' understanding not only of this particular form of myopathy, but of general muscle biology and other muscle diseases as well.
About the new findings
The new findings, published online Nov. 23, in the American Journal of Human Genetics, describe three mutations in the KBTBD13 gene that cause type 6 NM.
The researchers indicate that these mutations likely work via a different mechanism than the mechanisms underlying other types of nemaline myopathy.
Investigators studied 42 Australian-Dutch, Dutch, Spanish and Australian-Belgian patients who exhibited symptoms including impaired exercise tolerance, slowness of movement, abnormal gait, and slowly progressive muscle weakness of the neck and upper limb muscles.
Three mutations were found: one native to the Spanish group; the second exclusive to the Dutch, Australian-Dutch and Australian-Belgian study participants; and the third in a single individual from Australia.
All three mutations were shown to alter positively charged amino acids (protein components).
The researchers noted the presence in biopsy samples of both "rods" (threadlike clumps of protein in the muscle) and "cores," core-like structures running through the centers of muscle fibers akin to the lead running through the center of a pencil. The type 6 NM cores differed in appearance, with less sharply defined edges, from those observed in other forms of the disease.
The investigators described a “unifying feature” of type 6 NM: a greater proportion of enlarged or thickened "slow-twitch" muscle fibers, which are more efficient at generating fuel for use in prolonged exercise, and relatively fewer atrophic, or shrunken, "fast-twitch" fibers, which generate short bursts of energy but tire more rapidly. The investigators noted this pattern is characteristic in type 6 NM, and rarely observed in other subtypes of the disease.
The study team concluded that the KBTBD13 protein is most active in skeletal and heart muscle — although no heart abnormalities were observed in individuals with KBTBD13 gene defects.
"KBTBD13 is likely to have a significant, though as-yet-unknown, role in muscle structure and/or function," the study authors wrote.
Meaning for people with nemaline myopathy
Although no immediate potential exists for treatment from these new findings, a greater understanding of the functional role of the KBTBD13 protein in skeletal muscle will provide scientists with insight into the underlying mechanisms of type 6 NM and help focus efforts to pinpoint potential biological targets and develop drugs to hit them.
Near-term implications for these findings include the possibility of a genetic test for accurate diagnosis of the type 6 form of NM.