Scientists have identified a gene variant that seems to play a role in the age at which some patients with Duchenne muscular dystrophy (DMD) lose the ability to walk. The findings could help direct the development of therapeutics to treat the debilitating disorder, says Kevin M. Flanigan, MD, lead author of the study and a principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s Hospital.
The study, published in a recent issue of Annals of Neurology, is the latest finding from a multi-center effort to identify genetic modifiers involved in muscle disease. Leaders of that project include Dr. Flanigan at Nationwide Children’s and study coauthors Elizabeth McNally, MD, PhD, from the University of Chicago, and Robert Weiss, PhD, from the University of Utah.
For this study, Dr. Flanigan and his colleagues wanted to expand on studies of a gene called LTBP4, which was identified earlier by Dr. McNally as a potential modifier of muscle disease severity in mice. To find out if the gene had a similar role in humans with DMD, Dr. Flanigan studied LTBP4 in 254 patients with DMD who lost the ability to walk by age 20.
LBTP4 produces a protein that plays a key role in the regulation of TGF-beta, a cytokine involved in promoting inflammation and fibrosis—both of which occur as features of the profound muscle degeneration in patients with DMD. Although its exact role in muscular dystrophy is unclear, studies show that TGF-beta is upregulated in muscles of patients with DMD.
There are two main variants of the LTBP4 gene, one more common than the other. The less common variant seemed to be protective for walking, says Dr. Flanigan, who also is a neurologist at Nationwide Children’s and a professor of pediatrics at The Ohio State University.
“Boys who carry two copies of the less common variant walk longer than those boys who carry either two copies of the more common variant, or one copy of each,” he says.
“The only currently available medications that have been shown to influence the course of the disease are corticosteroids such as prednisone, which extend the ability to walk on the order of one to three years,” says Dr. Flanigan, adding that the study found that boys who had never received steroids but who had the protective variant retained the ability to walk as long as boys without the variant who had received treatment with steroids. “Our results suggest that the effect of LTBP4 variation is on a scale that is comparable to that of the steroid effect, and in fact that the protective effect of the minor LTBP4 allele is greatest in boys treated with steroids, suggesting that part of the action of steroids may be related to LTBP4 function,” he says.
The genetic samples analyzed in this study are part of the United Dystrophinopathy Project, an archive of DNA and clinical data from nearly 1,000 patients with dystrophinopathy. The project was created with support from the National Institutes of Health and is based at Nationwide Children’s. Dr. Flanigan and Dr. Weiss are now working with Veronica Vieland, PhD, director of the Battelle Center for Mathematical Medicine at Nationwide Children’s, to probe the archive using mathematical approaches that she designed to identify gene modifiers.
“Our goal is to use the unique resource of the United Dystrophinopathy Project in order to identify molecular mechanisms that contribute to disease progression and potentially elucidate pathways amenable to therapeutic intervention,” Dr. Flanigan says.
Flanigan, KM, Ceco E, Lamar K, Kaminoh Y, Dunn DM, Mendell JR, King WM, Pestronk A, Florence JM, Mathews KD, Finkel RS, Swoboda KJ, Gappmaier E, Howard MT, Day JW, McDonald C, McNally EM, Weiss RB. LTBP4 Genotype Predicts Age of Ambulatory Loss in Duchenne Muscular Dystrophy. Annals of Neurology. Apr 2013, 73(4): 481-488.