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

Sci Transl Med 28 July 2010:
Vol. 2, Issue 42, p. 42ra54
DOI: 10.1126/scitranslmed.3000692
Research Article

A Human-Specific Deletion in Mouse Cmah Increases Disease Severity in the mdx Model of Duchenne Muscular Dystrophy
Kumaran Chandrasekharan1, Jung Hae Yoon1, Ying Xu2, Sarah deVries1, Marybeth Camboni1, Paulus M. L. Janssen2, Ajit Varki3 and Paul T. Martin1,2,4,*
+ Author Affiliations

1Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA.
2Department of Physiology and Cell Biology, Ohio State University College of Medicine, Columbus, OH 43210, USA.
3Departments of Medicine and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
4Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH 43205, USA.

*To whom correspondence should be addressed. E-mail: paul.martin@nationwidechildrens.org

Abstract
During the evolution of humans, an inactivating deletion was introduced in the CMAH (cytidine monophosphate–sialic acid hydroxylase) gene, which eliminated biosynthesis of the common mammalian sialic acid N-glycolylneuraminic acid from all human cells. We found that this human-specific change in sialylation capacity contributes to the marked discrepancy in phenotype between the mdx mouse model for Duchenne muscular dystrophy (DMD) and the human disease. When compared to human patients with DMD, mdx mice show reduced severity or slower development of clinically relevant disease phenotypes, despite lacking dystrophin protein in almost all muscle cells. This is especially true for the loss of ambulation, cardiac and respiratory muscle weakness, and decreased life span, all of which are major phenotypes contributing to DMD morbidity and mortality. These phenotypes occur at an earlier age or to a greater degree in mdx mice that also carry a human-like mutation in the mouse Cmah gene, possibly as a result of reduced strength and expression of the dystrophin-associated glycoprotein complex and increased activation of complement. Cmah-deficient mdx mice are a small-animal model for DMD that better approximates the human glycome and its contributions to muscular dystrophy.

Footnotes
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).

Copyright © 2010, American Association for the Advancement of Science

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