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Neuromol Med (2013) 15:180191 DOI 10.1007/s12017-012-8209-7
ORIGINAL PAPER
Variable Phenotypes of Knockin Mice Carrying the M712T Gne Mutation
Ilan Sela Lena Yakovlev Michal Becker Cohen Moran Elbaz
Nurit Yanay Uri Ben Shlomo Hagit Yotvat Yakov Fellig Zohar Argov
Stella Mitrani-Rosenbaum
Received: 20 September 2012 / Accepted: 29 November 2012 / Published online: 13 December 2012 Springer Science+Business Media New York 2012
Abstract GNE myopathy is a recessive adult onset, slowly progressive distal and proximal myopathy, caused by mutations in the GNE gene. The most frequent mutation in GNE myopathy patients is the Middle Eastern founder mutation M712T. We have generated GneM712T/M712T knockin mice. A
high mortality rate in the rst generation due to renal failure was recorded (as previously described). However, the following GneM712T/M712T offspring generations could be clas
sied into 3 phenotypic categories: severe, mild and without apparent phenotype. By further crossing between mice with no apparent phenotype, we were able to establish a colony of Gne M712T/M712T knockin mice with a high- and long-term
survival rate, lacking any renal phenotype. These mice did not present any muscle phenotype (clinical or pathological) for up to 18 months. No correlation was found between the expression of any of the two mRNA Gne isoforms in muscle and the mouse genotype or phenotype. However, the expression of isoform 2 mRNA was signicantly higher in
the kidney of GneM712T/M712T kidney affected mice compared
with control. In contrast, the expression of UPR markers Bip, Chop and of the spliced form of XBP1, was upregulated in muscle of GneM712T/M712T mice compared with controls, but
was unchanged in the affected kidney. Thus, Gne defects can affect both muscle and kidney in mouse, but probably through different mechanisms.
Keywords GNE myopathy HIBM Knockin mouse
Renal disorder Gne isoforms Unfolded protein response
Introduction
The GNE gene encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (UDP-GlcNAc 2-epimerase/ManNAc kinase; GNE), which is the key enzyme in the sialic acid biosynthesis (Keppler et al. 1999). It catalyzes the rst two steps of the pathway; the formation of N-acetylmannosamine from UDP-N-acetylglucosamine and the consecutive phosphorylation of the sugar at C6. The epimerase activity is feedback inhibited by cytidine monophosphate sialic acid, the downstream product. Sialic acid, the most abundant terminal monosaccharide on glycoproteins and glycolipids of eukaryotic cells,is...