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

Authors

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

Publication/Presentation Date

3-1-2004

Abstract

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.

Volume

81

Issue

3

First Page

196

Last Page

202

ISSN

1096-7192

Published In/Presented At

Huizing, M., Rakocevic, G., Sparks, S. E., Mamali, I., Shatunov, A., Goldfarb, L., Krasnewich, D., Gahl, W. A., & Dalakas, M. C. (2004). Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. Molecular genetics and metabolism, 81(3), 196–202. https://doi.org/10.1016/j.ymgme.2003.11.012

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

14972325

Department(s)

Administration and Leadership

Document Type

Article