X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation

Area of Science:

• Genetics and Genomics
• Animal Models
• Biomedical Research

Background:

• Canine models of Duchenne muscular dystrophy (DMD) are crucial for preclinical therapy evaluation due to disease similarity.
• The Golden Retriever muscular dystrophy (GRMD) model is widely utilized, but new models are needed.
• This study introduces a novel spontaneous dystrophinopathy in Labrador Retrievers, termed Labrador Retriever muscular dystrophy (LRMD).

Purpose of the Study:

• To characterize a new spontaneous canine model of dystrophinopathy (LRMD).
• To compare the LRMD model with the established GRMD model.
• To identify the genetic mutation responsible for LRMD and explore its implications for DMD research.

Main Methods:

• Established a colony of LRMD dogs from spontaneous cases.
• Conducted functional tests on 14 LRMD dogs, comparing them to GRMD dogs.
• Utilized molecular techniques, including RNA-sequencing, to identify the causative mutation.

Main Results:

• LRMD dogs exhibited clinical features and functional test results comparable to GRMD dogs, with similar heterogeneity.
• A novel 2.2-Mb inversion disrupting the DMD gene and involving TMEM47 was identified as the causal mutation in LRMD.
• Ectopic expression of the Dp71 isoform was observed in skeletal muscle, and no significant polymorphisms were found in known modifier genes (LTBP4, Jagged1) or Pitpna mRNA levels.

Conclusions:

• The LRMD model is phenotypically equivalent to the GRMD model, presenting a valuable new tool for dystrophinopathy research.
• A novel large DNA mutation within the DMD gene has been identified in the LRMD model.
• The LRMD model provides a relevant platform for identifying additional DMD modifier genes.