title: Effect of genetic background on the dystrophic phenotype in mdx mice.
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.
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Coley
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bogdanik
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA, Department of Integrative Systems Biology, George Washington University School of Medicine, Washington, DC, USA.
authors.forename: Maria Candida
authors.initials: MC
authors.lastname: Vila
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Van Der Meulen
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Novak
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Nearing
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Quinn
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Allison
authors.initials: A
authors.lastname: Saunders
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Connor
authors.initials: C
authors.lastname: Dolan
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Whitney
authors.initials: W
authors.lastname: Andrews
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lammert
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Austin
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Terence A
authors.initials: TA
authors.lastname: Partridge
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA and knagaraju@childrensnational.org cat.lutz@jax.org.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Lutz
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA, Department of Integrative Systems Biology, George Washington University School of Medicine, Washington, DC, USA knagaraju@childrensnational.org cat.lutz@jax.org.
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D004452:Echocardiography; D005260:Female; D000068617:Genetic Background; D018737:Hand Strength; D006334:Heart Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D009132:Muscles / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology; D009210:Myofibrils / Q000473:pathology; D009220:Myositis / Q000235:genetics / Q000473:pathology; D009929:Organ Size; D010641:Phenotype
chemical_list: D016189:Dystrophin