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Genetic modifiers of DMD disease severity identified in humans for the first time

ICNA
Updated

In pioneering research published in the Jan 18 issue of Neurology Pegoraro et al reports the identification of genetic modifiers of muscular dystrophy in humans for the first time.

Duchenne muscular dystrophy is a severe X-linked disease caused by mutations in the DMD gene that lead to nearly complete loss of dystrophin in skeletal and cardiac muscle.

In pioneering research published in the Jan 18 issue of Neurology Pegoraro et al reports the identification of genetic modifiers of muscular dystrophy in humans for the first time.The authors used informatics approaches, based on their earlier studies in normal subjects and from comparisons of rapid vs slow progression in DMD, to select a limited set of 29 candidate polymorphisms for analysis. One of the polymorphisms is a previously known single base variant in the promoter region of SPP1, and the authors provide evidence that the G allele of rs28357094 (observed in 35% of cases) is associated with more severe disease, as measured by either time to continuous wheelchair use or grip strength in 2 independent cohorts. The severe allele is present in about a third of all people, so this single allele could account for a substantial portion of the variability in disease progression.

In an accompanying editorial Drs Stanley F. Nelson and Robert C. Griggs point out that the presence of the G allele may provide a basis for stratifying patients entering clinical trials according to the anticipated rate of disease progression. This may improve the power of the trial by reducing interindividual heterogeneity, thereby permitting clinicians to select the relatively rapidly progressing subjects who may respond better to therapy.

In addition, the SPP1 variants associated with disease severity in DMD suggest the possibility of osteopontin as a rational therapeutic target.Osteopontin is a cytokine that promotes immune cell migration and survival; high tissue and circulating levels of osteopontin have been identified in a variety of muscular dystrophies, various inflammatory disorders, and cancer.

Studies of osteopontin knockout models have shown lessened severity and fibrosis in the mdx mouse. Interestingly however the G allele, associated with low osteopontin expression in mice and less disease seems to be associated with more severe disease in humans as shown by Pegoraro et al.

While hailing the findings of this study Drs Stanley F. Nelson and Robert C. Griggs also point out the importance of replicating these findings in larger cohort of DMD boys.It is indeed likely that all observed variations in DMD disease severity were not due to SPP1 variants.

With relatively inexpensive comprehensive sequencing of the human genome now made possible, this study should pave the way for more genome wide searches of disease modifiers as in the case of the recent identification of the IFRD1 variant in cystic fibrosis.


SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy E. Pegoraro, E.P. Hoffman, L. Piva, B.F. Gavassini, S. Cagnin, M. Ermani, L. Bello, G. Soraru, B. Pacchioni, M.D. Bonifati, G. Lanfranchi, C. Angelini, A. Kesari, I. Lee, H. Gordish-Dressman, J.M. Devaney, C.M. McDonald On behalf of the Cooperative International Neuromuscular Research Group Neurology 2011;76 219-226
Predicting the severity of Duchenne muscular dystrophy: Implications for treatment Stanley F. Nelson and Robert C. Griggs Neurology 2011;76 208-20

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