Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations

Marjan Huizing, Goran Rakocevic, Susan E Sparks, Ioanna Mamali, Alexey Shatunov, Lev Goldfarb, Donna Krasnewich, William A Gahl, Marinos C Dalakas

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)


Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular disorder associated with mutations in the gene UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose product is the rate limiting bi-functional enzyme catalyzing the first two steps of sialic acid biosynthesis. Loss of GNE activity in HIBM is thought to impair sialic acid production and interfere with proper sialylation of glycoconjugates, but it remains unclear how such a defect would lead to muscle destruction and muscle weakness. Hypoglycosylation of alpha-dystroglycan, a central protein of the skeletal muscle dystrophin-glycoprotein complex, results in disturbed interactions with extracellular matrix proteins. This has recently been identified as the pathomechanism involved in several congenital muscular dystrophies. We examined the glycosylation status of alpha-dystroglycan in muscle biopsies of four HIBM patients of non-Iranian Jewish origin (one American, two Indians, and one Greek). Two of these patients carry novel compound heterozygous GNE mutations on exon 2 and exon 9. All four muscle biopsies showed absent or markedly reduced immunolabeling with two different antibodies (VIA4 and IIH6) to glycosylated epitopes of alpha-dystroglycan. Normal labeling was found using antibodies to the core alpha-dystroglycan protein, beta-dystroglycan, and laminin alpha-2. These findings resemble those found for other congenital muscular dystrophies, suggesting that HIBM may be a "dystroglycanopathy," and providing an explanation for the muscle weakness of patients with GNE mutations.

Original languageEnglish
Pages (from-to)196-202
Number of pages7
Issue number3
Publication statusPublished - Mar 2004


  • Adult
  • Cytoskeletal Proteins
  • Dystroglycans
  • Extracellular Matrix Proteins
  • Female
  • Glycosylation
  • Humans
  • Laminin
  • Membrane Glycoproteins
  • Middle Aged
  • Multienzyme Complexes
  • Muscle, Skeletal
  • Mutation
  • Myositis, Inclusion Body
  • N-Acetylneuraminic Acid
  • Protein Binding
  • Journal Article


Dive into the research topics of 'Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations'. Together they form a unique fingerprint.

Cite this