Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) are devastating disorders. Both are associated with mutations in the dystrophin gene, a huge gene with 79 exons spread over 2.4 million bases of genomic sequence. Deletions of large portions of the gene account for around 60% of all dystrophin mutations. The remainder consist of point mutations (primarily premature stop codon mutations), small deletions resulting in shift of the reading frame, and (in less than 5%) duplications. We have developed the methodology to rapidly, robustly, and economically perform direct sequence analysis of the entire coding and regulatory regions of the dystrophin gene, greatly expediting the characterization of mutations in non-deleted dystrophinopathy patients. Using this methodology, we propose to characterize the mutations responsible for DMD and BMD in a large cohort of patients, from whom a standardized and thorough phenotypic characterization will be obtained. Phenotype/genotype information will be compiled in a dystrophinopathy registry/database. In addition to correlation of the genotype to the phenotype, we will determine the effect that specific mutations have on mRNA processing and translation, and the relationship of both the mutations context and its resultant molecular profile to disease phenotype. Finally, we will test the hypothesis that specific missense mutations imply the presence of as-yet uncharacterized dystrophin binding partners. Our catalogue of patient mutations will identify molecular pathways which influence disease pathogenesis, and may suggest novel targets for treatment. Although we do not propose to perform treatment trials at present, this proposed study will identify cohorts of patients who may be candidates for any future trials here or at other institutions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043264-09
Application #
7795700
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Porter, John D
Project Start
2002-09-20
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$911,883
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
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Vulin, Adeline; Wein, Nicolas; Strandjord, Dana M et al. (2014) The ZZ domain of dystrophin in DMD: making sense of missense mutations. Hum Mutat 35:257-64
Anthony, Karen; Arechavala-Gomeza, Virginia; Taylor, Laura E et al. (2014) Dystrophin quantification: Biological and translational research implications. Neurology 83:2062-9
Thrush, Philip T; Edward, Neeraj; Flanigan, Kevin M et al. (2013) Precordial R wave height does not correlate with echocardiographic findings in boys with Duchenne muscular dystrophy. Congenit Heart Dis 8:561-7
Flanigan, Kevin M; Ceco, Ermelinda; Lamar, Kay-Marie et al. (2013) LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol 73:481-8
Viollet, Laurence; Thrush, Philip T; Flanigan, Kevin M et al. (2012) Effects of angiotensin-converting enzyme inhibitors and/or beta blockers on the cardiomyopathy in Duchenne muscular dystrophy. Am J Cardiol 110:98-102
Flanigan, Kevin M; Dunn, Diane; Larsen, C Aaron et al. (2011) Becker muscular dystrophy due to an inversion of exons 23 and 24 of the DMD gene. Muscle Nerve 44:822-5
Flanigan, Kevin M; Dunn, Diane M; von Niederhausern, Andrew et al. (2011) Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene. Hum Mutat 32:299-308
Montes, J; McDermott, M P; Martens, W B et al. (2010) Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology 74:833-8

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