Journal
PHYSIOLOGICAL GENOMICS
Volume 43, Issue 1, Pages 24-31Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00172.2010
Keywords
skeletal muscle; heart; genetic modifiers; quantitative trait locus; fibrosis
Categories
Funding
- National Heart, Lung, and Blood Institute [R01-HL-61322, T32-HL-07381]
- Muscular Dystrophy Association
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007381, R01HL061322] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P01NS072027] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA021336] Funding Source: NIH RePORTER
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Distinct genetic regions modify specific muscle groups in muscular dystrophy. Physiol Genomics 43: 24-31, 2011. First published October 19, 2010; doi:10.1152/physiolgenomics.00172.2010.-Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein gamma-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied, including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci, possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9 and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single-gene disorders.
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