Journal
JOURNAL OF HUMAN GENETICS
Volume 51, Issue 5, Pages 397-406Publisher
SPRINGER TOKYO
DOI: 10.1007/s10038-006-0374-9
Keywords
DNA sequencing; muscle; muscular dystrophy; stem cells; zebrafish
Categories
Funding
- NINDS NIH HHS [P01 NS040828, P01 NS40828-01, P50 NS040828] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS040828, P01NS040828] Funding Source: NIH RePORTER
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The muscular dystrophies are a heterogenous group of graphically caused muscle degenerative disorders. The Kunkel laboratory has had a longstanding research program into the pathogenesis and treatment of these diseases. Starting with Our identification of dystrophin as the defective protein in Duchenne muscular dystrophy (DMD), we have continued Our work oil normal dystrophin function and how it is altered in Muscular dystrophy. Our work has led to the identification of the defective genes in three forms of limb girdle muscular dystrophy (LGMD) and a better understanding of how muscle degenerates in many of the different dystrophies. The identification of mutuations Causing human forms of dystrophy has lead to improved diagnosis for patients with the disease. We are Continuing to improve the molecular diagnosis of the dystrophies and have developed a high-throughput sequencing approach for the low-cost rapid diagnosis of all known forms of dystrophy. In addition. we are continuing to work oil therapies using available animal models. Currently, there are a number Of Mouse models of the human dystrophies. the most notable being the mdx Mouse with dystrophin deficiency. These mice are being used to test possible therapies, including stem-cell-based approaches. We have been able to systemically deliver human dystrophin to these mice via the arterial circulation and convert 8% of dystrophin-deficient fibers to fibers expressing human dystrophin. We are now expanding our research to identify new forms of LGMD by analyzing, zebrafish models of muscular dystrophy. Currently, we have 14 different zebrafish Mutants exhibiting various phenotypes Of muscular dystrophy, including muscle weakness and inactivity. One of these Mutants carries a stop codon mutation in dystrophin, and we have recently identified another carrying a mutation in titin. We are currently positionally Cloning the disease-causative Mutation in the remaining 12 mutant strains. We hope that one of these new mutant strains of fish will have a mutation in a gene not previously implicated in human muscular dystrophy. This gene would become a candidate gene to be analyzed in patients which do not carry a mutation in any of the known dystrophy-associated genes. By studying both disease pathology and investigating potential therapies, we hope to make a positive difference in the lives of People living With muscular dystrophy.
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