N-Glycolylneuraminic acid deficiency worsens cardiac and skeletal muscle pathophysiology in α-sarcoglycan-deficient mice

Glycobiology. 2013 Jul;23(7):833-43. doi: 10.1093/glycob/cwt020. Epub 2013 Mar 20.


Roughly 3 million years ago, an inactivating deletion occurred in CMAH, the human gene encoding CMP-Neu5Ac (cytidine-5'-monophospho-N-acetylneuraminic acid) hydroxylase (Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 95:11751-11756). This inactivating deletion is now homozygous in all humans, causing the loss of N-glycolylneuraminic acid (Neu5Gc) biosynthesis in all human cells and tissues. The CMAH enzyme is active in other mammals, including mice, where Neu5Gc is an abundant form of sialic acid on cellular membranes, including those in cardiac and skeletal muscle. We recently demonstrated that the deletion of mouse Cmah worsened the severity of pathophysiology measures related to muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy (Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT. 2010. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med. 2:42-54). Here, we demonstrate similar changes in cardiac and skeletal muscle pathology and physiology resulting from Cmah deletion in α-sarcoglycan-deficient (Sgca(-/-)) mice, a model for limb girdle muscular dystrophy 2D. These experiments demonstrate that loss of mouse Cmah can worsen disease severity in more than one form of muscular dystrophy and suggest that Cmah may be a general genetic modifier of muscle disease.

Keywords: dystroglycan; limb girdle; muscular dystrophy; sarcoglycan; sialic acid.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gene Deletion
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / metabolism
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Neuraminic Acids / metabolism*
  • Sarcoglycans / deficiency
  • Sarcoglycans / genetics*


  • Neuraminic Acids
  • Sarcoglycans
  • N-glycolylneuraminic acid