No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation.
Hereditary inclusion body myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, which is caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the biosynthetic pathway of sialic acid. In order to investigate the consequences of the mutated GNE enzyme in muscle cells, we have established cell cultures from muscle biopsies carrying either kinase or epimerase mutations. While all myoblasts carrying a mutated GNE gene show a reduction in their epimerase activity, only the cells derived from the patient carrying a homozygous epimerase mutation present also a significant reduction in the overall membrane bound sialic acid. These results indicate that although mutations in each of the two GNE domains result in an impaired enzymatic activity and the same HIBM phenotype, they do not equally affect the overall sialylation of muscle cells. This lack of correlation suggests that the pathological mechanism of the disease may not be linked solely to the well-characterized sialic acid pathway.
Salama
Ilan
I
Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Hinderlich
Stephan
S
Shlomai
Zipora
Z
Eisenberg
Iris
I
Krause
Sabine
S
Yarema
Kevin
K
Argov
Zohar
Z
Lochmuller
Hanns
H
Reutter
Werner
W
Dabby
Ron
R
Sadeh
Menachem
M
Ben-Bassat
Hannah
H
Mitrani-Rosenbaum
Stella
S
D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism*; D018979:Myositis, Inclusion Body / Q000201:enzymology* / Q000235:genetics*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*
D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D019158:N-Acetylneuraminic Acid