Résumé :
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Communication n° 442 Introduction. Hereditary Inclusion Body Myopathy (HIBM) is a unique group of adult onset neuromuscular disorders characterized by slowly progressive distal and proximal muscle weakness and typical muscle pathology including rimmed vacuoles and filamentous inclusions. The prototype form of HIBM, related to mutations in the gene encoding the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the biosynthetic pathway of sialic acid, is an autosomal recessive disorder particularly frequent in Middle Eastern Jews. Several missense mutations were identified in GNE in HIBM patients worldwide, whereas a unique homozygous mutation, M712T, was found in all Middle Eastern patients. Objectives and Methods. Despite intensive cellular and biochemical characterization of HIBM muscle cells, the pathophysiological pathway leading from GNE mutations to HIBM is poorly understood. In order to elucidate the first occurring downstream events of this pathway we have analyzed the genomic expression patterns of muscle specimens from 10 HIBM patients, carrying the M712T mutation, presenting mild histological changes, and 10 healthy individuals using the U133A Affymetrix microarray. Results. An initial Principal Component Analysis (PCA) emphasized the major role of age in clustering the analyzed individuals, whereas a subsequent analysis of the datasets by intersection of 3 statistical methods (t test, TNOM and INFO) identified 374 genes significantly differentially expressed between affected and healthy individuals, independently of age. Among those, a large number of overexpressed transcripts encoding proteins are involved in the oxidative phosphorylation cascade, ATP synthesis and metabolic pathways. Conclusions. To date GNE has been related solely to the sialic acid synthesis pathway, and no clear understanding of the cause/effect relationship between GNE mutations and HIBM phenotype could be provided. The identification of a relatively high number of genes related to mitochondrial processes overexpressed in HIBM affected muscles, if confirmed, could disclose new functions for GNE in muscle cells.
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