Mitochondrial processes are impaired in hereditary inclusion body myopathy

Iris Eisenberg, Noa Novershtern, Zohar Itzhaki, Michal Becker-Cohen, Menachem Sadeh, Peter H.G.M. Willems, Nir Friedman, Werner J.H. Koopman, Stella Mitrani-Rosenbaum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. To elucidate the pathological mechanisms leading from the mutated GNE to the HIBM phenotype, we attempted to identify and characterize early occurring downstream events by analyzing the genomic expression patterns of muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation and presenting mild histological changes, compared with 10 healthy matched control individuals, using GeneChip expression microarrays. When analyzing the expression profile data sets by the intersection of three statistic methods (Student's t-test, TNoM and Info score), we found that the HIBM-specific transcriptome consists of 374 differentially expressed genes. The specificity of the HIBM transcriptome was assessed by the minimal transcript overlap found between HIBM and the transcriptome of nine additional muscle disorders including adult onset limb girdle myopathies, inflammatory myopathies and early onset conditions. A strikingly high proportion (18.6%) of the overall differentially expressed mRNAs of known function were found to encode for proteins implicated in various mitochondrial processes, revealing mitochondria pathways dysregulation. Mitochondrial morphological analysis by video-rate confocal microscopy showed a high degree of mitochondrial branching in cells of HIBM patients. The subtle involvement of mitochondrial processes identified in HIBM reveals an unexpected facet of HIBM pathophysiology which could at least partially explain the slow evolution of this disorder and give new insights in the disease mechanism.

Original languageAmerican English
Pages (from-to)3663-3674
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number23
DOIs
StatePublished - 2008

Bibliographical note

Funding Information:
This work was supported by a grant from the German – Israeli Foundation for Research and Development (GIF), Jerusalem, Israel, and in part by grants from the Association Francaise contre les Myopathies (AFM) and from the Neuromuscular Disease Foundation (NDF).

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