Effect of genetic background on the dystrophic phenotype in mdx mice.
Document Type
Article
Publication Date
1-1-2016
Keywords
Animals, Body Weight, Disease Models, Animal, Dystrophin, Echocardiography, Female, Genetic Background, Hand Strength, Heart Function Tests, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred mdx, Muscle Contraction, Muscles, Muscular Dystrophy, Animal, Myofibrils, Myositis, Organ Size, Phenotype
JAX Source
Hum Mol Genet 2016; 25(1):130-145.
Volume
25
Issue
1
First Page
130
Last Page
145
ISSN
1460-2083
PMID
26566673
Grant
W81XWH-11-1-0330
Abstract
Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits. Hum Mol Genet 2016; 25(1):130-145.
Recommended Citation
Coley W,
Bogdanik LP,
Vila M,
Yu Q,
Van Der Meulen J,
Rayavarapu S,
Novak J,
Nearing M,
Quinn J,
Saunders A,
Dolan C,
Andrews W,
Lammert C,
Austin A,
Partridge T,
Cox GA,
Lutz C,
Nagaraju K.
Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet 2016; 25(1):130-145.