Gene Variant May Indicate Severity of DMD

A variant in the gene for the osteopontin protein has the potential to help predict disease course in Duchenne MD

Article Highlights:
  • A team of scientists has uncovered a natural variant in a section of the gene for a protein called osteopontin that may predict disease severity in most cases of Duchenne muscular dystrophy (DMD).
  • The presence of the variant appears to correlate with more rapid disease progression, earlier loss of the ability to walk, significantly greater weakness in the arms and legs, and decreased grip strength, compared to findings in patients who don't have it.
  • In this study, 35 percent of the patients were found to have the variant.
  • If the findings are confirmed, they are expected to facilitate prediction of the probable course of DMD cases; allow researchers to plan and conduct more powerful clinical trials; and suggest targets for possible DMD therapies.
by Amy Madsen on January 11, 2011 - 2:58pm

A team of scientists working in the United States and Italy has uncovered a variant in the gene for a protein called osteopontin that appears to reliably indicate disease severity in most (but likely not all) cases of Duchenne muscular dystrophy (DMD).

The variant is apparently a genetic modifier of DMD, a disease in which the underlying cause is a mutation in the gene for the dystrophin protein and the resulting lack of dystrophin in the muscles.

By enabling scientists to better predict disease course in individual patients, identification of osteopontin as a genetic modifier in DMD has the potential to help streamline clinical trials. It may also have implications for the development of treatments aimed at modifying osteopontin or related substances.

About the new findings

Elena Pegoraro at the University of Padova in Italy, and Eric Hoffman, at Children's National Medical Center in Washington, D.C., coordinated the study team, which published its findings online Dec. 23, 2010, in Neurology.

MDA did not fund this study, but Hoffman has a current MDA grant for related work.

The Italian investigators studied 106 individuals with DMD, while researchers in Washington, D.C., belonging to the Cooperative International Neuromuscular Research Group (CINRG), studied another group of 156.

The investigators found a genetic modifier (a biological component that influences a disease, but is distinct and unrelated to its underlying molecular cause) in a particular location in the osteopontin gene. The modifier is a variant, known as the "G allele," found in approximately 35 percent of the DMD cases in this study. The G allele is a normal variant to the "T allele" typically found in that particular position in the osteopontin gene.

Trial participants with the G variant lost their ability to walk earlier, had significantly weaker limbs, and exhibited decreased grip strength, as compared with those whose osteopontin gene carried the T allele. The investigators also noted that the G allele correlated with more rapid disease progression.

About the G variant

The osteopontin gene carries instructions for production of osteopontin, a type of cell-signaling protein called a cytokine. Osteopontin is believed to encourage tissue inflammation and fibrosis (scarring), which are considered harmful effects in DMD. It may also influence muscle remodeling, however, which would be helpful in DMD.

The precise effect of the G variant on osteopontin production is unclear.

Previous studies have shown that osteopontin is elevated in muscle in humans with DMD and in mice with a DMD-like disease. Elevated osteopontin levels also are found in Becker muscular dystrophy (BMD), types 2A and 2B limb-girdle muscular dystrophy (LGMD) and in mouse models of muscular dystrophy.

In a 2009 study in mice with a DMD-like disease, researchers suggested that it's possible "osteopontin promotes inflammation and contributes to the deposition of scar tissue in the muscles of individuals with DMD, and that blocking it, or lowering its levels, may have the potential to be developed into a promising therapeutic." (See Fighting the Fire.)

Meaning for people with DMD

If the new findings are borne out in future studies, a number of positive implications are expected to follow:

  • Researchers and clinicians will be able to better assess how a particular individual's DMD is likely to progress.
  • It will be easier for researchers to identify similarly affected patients and sort them into well-matched groups of trial participants; this in turn should lead to more powerful, efficient and informative clinical trials.
  • New targets associated with osteopontin may be identified for therapeutic development.

Editor's note (1/24/11): An earlier version of this article stated that the G allele variant appears to reduce osteopontin protein levels. However, this has not been conclusively demonstrated.



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