New research has shown that a change in a gene not previously connected to type 2C limb-girdle muscular dystrophy (LGMD2C) modifies the severity of the disease in mice and is likely to do the same in people with this and perhaps with related types of muscular dystrophy.
The gene, called LPTB4, influences two processes: muscle-tissue scarring, and fragility of the membrane that surrounds each muscle fiber, reports study coordinator Elizabeth McNally, who has MDA funding for related work at the University of Chicago.
Research was conducted using mice missing the muscle protein known as gamma-sarcoglycan, the same protein missing in people with LGMD2C. People with this disease and other muscular dystrophies, particularly Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and the 2D, 2E and 2F forms of LGMD, have fragile muscle-fiber membranes and develop scar tissue in their muscles.
"In the families I see with muscular dystrophy, I have always been interested in trying to determine what makes one family member better and another person worse," McNally said. "Some patients continue walking much longer than others. We think this new gene, LPTB4, could help explain why some people do better. We also hope this new gene points to an angle we can develop as a therapy."
McNally has received several MDA research grants for related work and is a member of the Association's Scientific Advisory Committee. The study results were published online Nov. 2, 2009, in the Journal of Clinical Investigation.
About LGMD, DMD and BMD
Some forms of muscular dystrophy (i.e., DMD, BMD and several types of LGMD) are due to deficiencies of proteins associated with the membranes that surround each muscle fiber. These deficiencies lead to membrane damage. McNally's group uncovered an apparent link between membrane damage and muscle-fiber scarring (fibrosis), another aspect of these diseases. Both these harmful effects can be mitigated by a change in the LTBP4 gene.
Limb-girdle muscular dystrophy types 2C, 2D, 2E and 2F are caused by a deficiency of any of four sarcoglycan proteins, all of which normally help protect the muscle fibers from damage during muscle contraction.
DMD and BMD are due to a deficiency of dystrophin, another protein associated with the muscle fiber membrane.
All of these types of muscular dystrophy cause damage to the membranes around each muscle fiber, followed by loss of muscle and its replacement by scar tissue. However, disease severity varies to some extent, even in people with the same primary genetic defect.
About the new findings
McNally and colleagues speculated that background genes could influence whether the mouse model of LGMD2C had a mild or severe disease course.
The research team wanted to learn what gene or genes influence disease severity. They used a "genome-wide" (all genes) mapping strategy to find genes involved in scar formation and damage to the membrane surrounding each muscle fiber in muscular dystrophy.
They found, to their surprise, that one gene, the one that carries instructions for the LTBP4 protein, seems to be responsible for making muscular dystrophy milder, at least in the LGMD2C mice.
LTBP4 sticks to another protein, called TGF-beta, releasing it a little at a time and regulating its activity in cells. TGF-beta, a signaling protein, is known to play a major role in stimulating fibrosis and, according to the new findings, exacerbates membrane damage as well.
McNally's team found that the milder muscle disease was caused by unique changes in LTBP4 that caused it to more tightly hang on to TGF-beta. Without as much TGF-beta, the surrounding muscle cells were more stable and less likely to become scarred.
"TGF-beta signaling has both beneficial and detrimental effects," the authors note, "and thus, exploiting TGF-beta for therapy has a complicated side-effect profile." They say reducing TGF-beta signaling indirectly, by targeting LTBP4, could potentially allow for good control of the location and level of TGF-beta signaling in cells.
Meaning for people with MD
Many strategies, including transfer of genes or proteins, modification of interpretation of genes by cells, and combating inflammation with corticosteroids and experimental compounds, are in development to treat muscular dystrophies.
Regulating signaling by TGF-beta could one day be a relatively safe way to stabilize muscle and reduce scarring, two critical problems in muscular dystrophy.
In addition, the human LTBP4 gene has a number of naturally occurring changes in it, and these changes may help predict whose disease will be milder and whose will be more severe.
"We are very interested in learning whether these normal changes in LTBP4 indicate the disease path in human patients with muscular dystrophy, and also in using this genetic information to design new therapies based on our findings," McNally said.
The results of the new findings will need further confirmation in laboratory animals and ultimately will need to be tested in humans before a drug based on this approach can be taken to the U.S. Food and Drug Administration for approval.