Since the initial identification of mutations in the dystrophin gene as the cause of Duchenne and Becker muscular dystrophies, molecular genetics has provided a plethora of new information and insights into the pathogeneses of muscle diseases. In particular, our understanding of the limb-girdle muscular dystrophies (LMGD) have been greatly enhanced. Fourteen forms of LGMD have been identified; of these, specific gene have been characterized in ten. This goal of this proposal is to identify the molecular genetic basis of a fifteenth form of LGMD which has been transmitted in an autosomal dominant fashion in a large Spanish pedigree (Spanish autosomal dominant LGMD [SAD- LGMD]). The disease locus has been mapped to a seven centimorgan region of chromosome 7q31.3-32 with a maximum two-point LOD score of 7.59 with marker D7S2519. We will attempt to reduce the size of the disease locus by fine mapping studies. Candidate genes will be screened until the disease mutation is identified. The pathogenesis of the disease will be studied by studying the expression of the gene messenger RNA and the gene product in the patients' skeletal muscle and in tissue culture using cells from patients. A mouse model of the disease will be produced to further investigate the pathogenesis. Muscle biopsies from more than 50 patients with LGMD of unknown etiology will be screened for defects of the SAD-LGMD gene product. The identification of the cause of SAD-LGMD will expand our understanding of the disease and will likely enhance our general understanding of skeletal muscle functions and structure. For the patients, achieving the proposed goals will allow more accurate prenatal diagnosis, genetic counseling, and perhaps contribute to more rational therapies in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR047989-02S1
Application #
6653674
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Lymn, Richard W
Project Start
2001-09-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$9,762
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Emmanuele, Valentina; Kubota, Akatsuki; Garcia-Diaz, Beatriz et al. (2015) Fhl1 W122S causes loss of protein function and late-onset mild myopathy. Hum Mol Genet 24:714-26
Melia, Maria J; Kubota, Akatsuki; Ortolano, Saida et al. (2013) Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. Brain 136:1508-17
Palenzuela, L; Andreu, A L; Gamez, J et al. (2003) A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2. Neurology 61:404-6
Vu, Tuan H; Hirano, Michio; DiMauro, Salvatore (2002) Mitochondrial diseases. Neurol Clin 20:809-39, vii-viii