Duchenne muscular dystrophy (DMD), the most prevalent of more than twenty types of genetic disorder that result in progressive muscle weakness, is caused by a mutation in the gene that encodes the protein, dystrophin. Dystrophin forms one subunit of a glycoprotein complex that acts as a structural scaffold linking the extracellular matrix to the intracellular cytoplasm. Without dystrophin, the muscle fibre membranes become damaged by the large mechanical forces experienced by contractile tissues and the muscle fibres eventually die. Since the gene for dystrophin is on the X chromosome, only boys are affected and, although the disorder is predominantly one of muscle degeneration, some boys also have learning or behavioural difficulties.
Mice which have a loss-of-function mutation in the dystrophin gene (mdx mice) are used as a model for human DMD but new research led by scientists at King’s College London and funded by the Muscular Dystrophy Campaign suggests that these animals may not be suitable for studying the neurological effects of human DMD. The study looked at the genes for other proteins that make up the dystrophin glycoprotein complex and found significant differences between mice and humans. The main heterodimeric partner of dystrophin at the heart of the glycoprotein complex is α-dystrobrevin, which can exist in a substantial number of isoforms as a result of complex transcriptional and post-transcriptional regulation. The different isoforms of α-dystrobrevin influence the recruitment of other proteins into the dystrophin glycoprotein complex, leading to variations in structure and function. The researchers found that mouse, rat and hamster brains have fewer than half the number of α-dystrobrevin isoforms found in the brains of most other mammals (including humans), suggesting that there are likely to be fundamental differences between the dystrophin glycoprotein complexes of mice and humans, and calling into question the current use of mice to model neurological aspects of human DMD. Guinea pigs appear to be more similar to humans in terms of α-dystrobrevin isoforms and may provide a more suitable model.
The study is published in BMC Biology.