Research Team Finds Gene Causing Two Types Of Muscular Dystrophy

September 01, 1998

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.

Massachusetts General Hospital

Related Muscular Dystrophy Articles from Brightsurf:

Using CRISPR to find muscular dystrophy treatments
A study from Boston Children's Hospital used CRISPR-Cas9 to better understand facioscapulohumeral muscular dystrophy (FSHD) and explore potential treatments by systematically deleting every gene in the genome.

Duchenne muscular dystrophy diagnosis improved by simple accelerometers
Testing for Duchenne muscular dystrophy can require specialized equipment, invasive procedures and high expense, but measuring changes in muscle function and identifying compensatory walking gait could lead to earlier detection.

New therapy targets cause of adult-onset muscular dystrophy
The compound designed at Scripps Research, called Cugamycin, works by recognizing toxic RNA repeats and destroying the garbled gene transcript.

Gene therapy cassettes improved for muscular dystrophy
Experimental gene therapy cassettes for Duchenne muscular dystrophy have been modified to deliver better performance.

Discovery points to innovative new way to treat Duchenne muscular dystrophy
Researchers at The Ottawa Hospital and the University of Ottawa have discovered a new way to treat the loss of muscle function caused by Duchenne muscular dystrophy in animal models of the disease.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy
Massachusetts General Hospital researchers have found that extracellular RNA in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level.

Tamoxifen and raloxifene slow down the progression of muscular dystrophy
Steroids are currently the only available treatment to reduce the repetitive cycles of inflammation and disease progression associated with functional deterioration in patients with muscular dystrophy (MD).

Designed proteins to treat muscular dystrophy
The cell scaffolding holds muscle fibers together and protects them from damage.

Gene-editing alternative corrects Duchenne muscular dystrophy
Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

GW researcher finds genetic cause of new type of muscular dystrophy
George Washington University & St. George's University of London research, published in The American Journal of Human Genetics, outlines a newly discovered genetic mutation associated with short stature, muscle weakness, intellectual disability, and cataracts, leading researchers to believe this is a new type of congenital muscular dystrophy.

Read More: Muscular Dystrophy News and Muscular Dystrophy Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to