Limb-girdle muscular dystrophy (LGMD) is a class of muscular dystrophies characterized by progressive proximal skeletal muscle weakness and a distinct pattern of abnormalities on muscle biopsy. However, the LGMDs have a number of genetic causes and an array of different clinical outcomes. The quality of life has improved significantly for affected individuals, due primarily to supportive treatment, but currently no cur is available. A significant proportion of individuals affected by LGMD do not have mutations in the known genes, indicating that several causative genes for LGMD have yet to be discovered. The search for these genes has until recently been difficult, as many affected individuals represent sporadic cases, and thus potential LOD scores would be low and linkage scans would yield many candidates genes. The rapid advances in next generation sequencing technology is lowering these barriers, and will change many assumptions about genetic diagnosis in the research and clinical realms. Next generation sequencing will enable researchers and clinicians to identify causative mutations in sporadic cases as well as larger families that yield broad, low, or multiple linkage peaks with an abundance of candidate genes. The investigator along with his laboratory and his collaborators, have enrolled many kindreds affected by LGMD. Several of these families have a high likelihood of yielding novel causative genes. This combined approach, using both linkage analysis and next generation sequencing, is a powerful one that will broaden our knowledge of the muscular dystrophies. Next generation sequencing is already being applied in clinical settings, and a better understanding of the strengths and limitations of this technology will be important to grasp to make the greatest use of its potential.

Public Health Relevance

This proposal involves the use of next generation sequencing technology, linkage analysis, and animal models to identify and study novel causative genes for limb-girdle muscular dystrophy (LGMD). The project has the potential to provide new knowledge that will benefit scientists, physicians, and patients for two reasons: (1) identification of diseae-causing genes will improve our knowledge of the muscular dystrophies, and may lead to new approaches to therapy for these disorders;and (2) refinement of the diagnostic process using next generation sequencing technology will have broad applicability to many types of human diseases. Advances in the interpretation of these data in the research setting will have a major impact on the clinical realm, and thus the project is expected to generate significant benefits in the fields of neurology and genetics in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS080929-01A1
Application #
8578930
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Porter, John D
Project Start
2013-05-01
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$397,865
Indirect Cost
$165,481
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Mitsuhashi, Satomi; Mitsuhashi, Hiroaki; Alexander, Matthew S et al. (2013) Cysteine mutations cause defective tyrosine phosphorylation in MEGF10 myopathy. FEBS Lett 587:2952-7
Mitsuhashi, Satomi; Boyden, Steven E; Estrella, Elicia A et al. (2013) Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2. Neuromuscul Disord 23:975-80