Τίτλος:
Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM
due to GNE mutations
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. Published by Elsevier Inc.
Συγγραφείς:
Huizing, M
Rakocevic, G
Sparks, SE
Mamali, L
Shatunov, A
and Goldfarb, L
Krasnewich, D
Gahl, WA
Dalakas, MC
Περιοδικό:
Molecular Genetics and Metabolism
Εκδότης:
ACADEMIC PRESS INC ELSEVIER SCIENCE
Λέξεις-κλειδιά:
hereditary inclusion body myopathy; O-mannosylation; dystroglycan;
sialic acid; GNE; muscular dystrophy; dystrophin-glycoprotein complex
DOI:
10.1016/j.ymgme.2003.11.012
