title: A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy.
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.
authors.affiliation: Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Chandrasekharan
authors.forename: Jung Hae
authors.initials: JH
authors.lastname: Yoon
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Sarah
authors.initials: S
authors.lastname: deVries
authors.forename: Marybeth
authors.initials: M
authors.lastname: Camboni
authors.forename: Paulus M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Paul T
authors.initials: PT
authors.lastname: Martin
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D008817:Mice, Mutant Strains; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology*; D012720:Severity of Illness Index
chemical_list: D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase