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:
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.