Research ArticleMuscular Dystrophy

A Human-Specific Deletion in Mouse Cmah Increases Disease Severity in the mdx Model of Duchenne Muscular Dystrophy

Science Translational Medicine  28 Jul 2010:
Vol. 2, Issue 42, pp. 42ra54
DOI: 10.1126/scitranslmed.3000692

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A Sweet Deal for Mice

We don’t normally think of lab animals as lucky, but in some sense, mdx mice—a primary model for studying Duchenne muscular dystrophy (DMD)—are more fortunate than their human counterparts. Both mdx mice and boys with DMD have recessive mutations in the X-linked dystrophin gene that result in loss of the dystrophin protein in muscle cells. Whereas boys with DMD develop severe muscle weakness and lose the ability to walk before adolescence, the mdx mice don’t exhibit serious limb muscle wasting until old age. Furthermore, DMD patients generally die in their teens or twenties, but the mdx mice live nearly as long as their healthy siblings. Why is the disease so much less severe in mice? Martin and colleagues speculated that differences between mice and humans in the chains of sugars, or glycans, that coat the cell surface might play a role. Dystrophin, a cytoskeletal protein, interacts with glycated transmembrane proteins; this complex links the muscle’s actin fibers to the extracellular matrix.

Because pathogens such as viruses and bacteria often bind to cell surface glycans to gain entry into the cell, these sugar chains are prone to modification during natural selection, leading to a great deal of variability between mammalian species. For example, because of a mutation in the CMAH gene, humans fail to produce a particular monosaccharide—Neu5Gc—that normally resides on the ends of glycan structures. In most other mammals, including mice, this gene is functional and Neu5Gc is produced.

Martin and co-workers tested whether CMAH gene function affects disease pathology by introducing a mutation, similar to that in humans, into the Cmah gene in mdx mice. Such double-mutant mice developed symptoms of muscular dystrophy earlier and more severely than the mdx mice, making their disease progression more like that in humans. The authors also found that glycans containing Neu5Gc bind more tightly to the extracellular matrix than those without, providing one possible model for the effects of a lack of CMAH: reduced binding of the dystrophin-associated glycoproteins to the extracellular matrix. Additionally, dietary Neu5Gc—from foods such as red meat—might accumulate in muscle fibers and induce an immune reaction against these cells, because Neu5Gc is detected as a foreign antigen in animals that do not produce it. This idea, which is supported by the work of Martin, Varki, and co-workers, raises the possibility of modulating diet as a potential therapy for DMD.


  • Citation: K. Chandrasekharan, J. H. Yoon, Y. Xu, S. deVries, M. Camboni, P. M. L. Janssen, A. Varki, P. T. Martin, A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci. Transl. Med. 2, 42ra54 (2010).