Genetic background influences muscular dystrophy

Ahlke Heydemann, Jill M. Huber, Alexis Demonbreun, Michele Hadhazy, Elizabeth M. McNally*

*Corresponding author for this work

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Mutations in the genes encoding dystrophin and its associated proteins, the sarcoglycans, lead to muscular dystrophy in humans and in mouse models. In the presence of identical gene mutations, the muscular dystrophy phenotype can be highly variable. Using a mouse model of limb girdle muscular dystrophy engineered with a null allele of γ-sarcoglycan, we bred the identical γ-sarcoglycan mutation into four different genetic backgrounds. We found that the γ-sarcoglycan mutation is least severe in the129SV/J (129) strain and most severe on the DBA 2J JAX (DBA) strain using quantitative measures of Evan's blue dye uptake, as a marker of membrane permeability defects, and hydroxyproline content, as a marker of fibrosis. In addition we show that the DBA mice are most severely affected regardless of gender and age. The enhanced phenotype observed in the DBA strain was not caused by exercise as the DBA mice scored the lowest in a voluntary activity test. The milder phenotype seen in the 129SV/J and C57B6/J strains suggests that these backgrounds contain modifier loci that partially suppress the muscular dystrophy phenotype. Identification of these modifier genes and the associated pathways may lead to novel therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)601-609
Number of pages9
JournalNeuromuscular Disorders
Volume15
Issue number9-10
DOIs
StatePublished - Oct 1 2005

Keywords

  • Dystrophin
  • Genetic modifier
  • Muscular dystrophy
  • Sarcoglycan

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)

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