Research Team Finds Gene Causing Two Types Of Muscular Dystrophy

BOSTON -- An international research team based at the Massachusetts General Hospital (MGH) has discovered a gene that, when mutated, causes two types of muscular dystrophy. The gene found on chromosome 2 codes for a novel protein called dysferlin, produced in skeletal muscles. Mutations in dysferlin were seen in several families in which members had either Miyoshi myopathy, a very rare muscle disorder, or one form of limb girdle muscular dystrophy, a more common condition. The report appears in the September issue of Nature Genetics.

"It's an interesting twist that this gene is associated with two forms of muscular dystrophy," says Robert H. Brown Jr., MD, director of the Day Neuromuscular Research Laboratory at the MGH and leader of the study. "We started working on what we thought was a very rare, orphan disease and found that our work also applied to a more abundant form. It appears that 5 to 10 percent of cases of muscular dystrophy may result from mutations in this gene." He adds that identifying the gene will help improve diagnosis of these particular disorders and eventually could lead to treatment methods that address specific muscle defects.

The muscular dystrophies are genetic diseases characterized by progressive weakness and deterioration of the skeletal muscles, which control movement. There are nine major forms of muscular dystrophy, some of which include several distinct diseases; more than 20 gene defects have been associated with the various types. While some of the more common forms appear in childhood, other forms may produce symptoms that appear in adolescence or adulthood. The progression and prognosis of the disorder, along with the particular muscles affected, depend on the specific form of muscular dystrophy.

"We're very encouraged by this finding," says Leon Charash, MD, chairman of the Medical Advisory Committee of the Muscular Dystrophy Association. "We are about to embark on safety trials in gene therapy for some of the muscular dystrophies, and finding new genes means more possibilities for intervention using gene therapy."

The current discovery caps a process that began 15 years ago when Brown met with members of a family affected by an unusual muscle disease characterized by weakness appearing in the lower legs in early adulthood. Searching the medical literature, Brown and his colleagues found only one description of a similar disorder, first reported internationally by Professor Kazuo Miyoshi of Japan in 1986. They named the family's disorder "Miyoshi myopathy" (meaning a disorder of muscle).

Because the disorder was so rare, Brown's team worked with collaborators from around the world to search for other families with the same problem. Eventually the project included researchers from Spain, France, Italy, Tunisia, Saudi Arabia, Canada and Japan, as well as from other US institutions. In 1995, members of the team first mapped the Miyoshi myopathy gene to chromosome 2. At the same time, researchers from the University of Newcastle in England mapped to the same area the gene for one type of limb girdle muscular dystrophy (LGMD-2B) characterized by weakness that begins in the hips and shoulders. Subsequent work by other groups described families in which both disorders apparently appeared.

Using standard techniques for identifying disease-associated genes, Brown's team narrowed down the portion of chromosome 2 where the gene might lie and identified five candidate genes in that area that were expressed in skeletal muscle tissue. Using information from several families with Miyoshi myopathy, they identified nine mutations in the gene later named dysferlin that were found in people with either Miyoshi myopathy or LGMD-2B.

The researchers were surprised to find that, in one family, a brother had Miyoshi myopathy but his sisters had LGMD-2B, although they all had the same dysferlin mutation. Two other families carried identical mutations -- perhaps because of an unknown, distant relationship; but affected individuals in one family developed Miyoshi myopathy, while those in the other family had a slightly different form in which weakness began in the front of the lower legs. The same issue of Nature Genetics also includes a report from the University of Newcastle group that further associates the dysferlin gene with LGMD-2B.

Jing Liu, PhD, of Brown's lab at the MGH says: "It's fascinating to see how the same mutation can be associated with different diseases. We now need to find out what other factors, either environmental or genetic, might be involved in determining exactly what symptoms result from a specific mutation." Liu, the first author of the Nature Genetics paper, now is with the Phage Tech company of Montreal.

Brown explains that the dysferlin protein may be involved in maintaining the membranes of structures within cells, that perform functions critical to the cells' activity. A similar protein found in the roundworm c. elegans causes defects in sperm when mutated. Brown notes that developing a mouse model with a defective dysferlin gene will help researchers on his team and elsewhere better understand the protein's function and develop strategies to treat these muscle disorders.

The research team also included scientists from Hospital Sant Pau in Barcelona, Spain; Roswell Park Cancer Institute in Buffalo, N.Y.; Hopital da la Salpetriere in Paris; University of Padova in Italy; La Rabta in Tunis, Tunisia; King Faisal Hospital in Riyadh, Saudi Arabia; University of Texas Health Science Center in San Antonio; Montreal General Hospital in Quebec; and the Japanese National Institute of Neuroscience in Tokyo. Among the numerous supporters of this research and the investigators are the Cecil B. Day Investment Company, the Muscular Dystrophy Association, the National Institutes of Health and the Medical Research Council of Canada.