title: Skeletal muscle gene expression profiling in mitochondrial disorders.
abstract: Extremely variable clinic and genetic features characterize mitochondrial encephalomyopathy (MEM). Pathogenic mitochondrial DNA (mtDNA) defects can be divided into large-scale rearrangements and single point mutations. Clinical manifestations become evident when a threshold percentage of the total mtDNA is mutated. In some MEM, the "mutant load" in an affected tissue is directly related to the severity of the phenotype. However, the clinical phenotype is not simply a direct consequence of the relative abundance of mutated mtDNA. Other factors, such as nuclear background, can contribute to the disease process, resulting in a wide range of phenotypes caused by the same mutation. Using Affymetrix oligonucleotide cDNA microarrays (HG-U133A), we studied the gene expression profile of muscle tissue biopsies obtained from 12 MEM patients [4 common 4977 bp deleted mtDNA and 8 A3243G: 4 progressive external ophthalmoplegia (PEO) and 4 mitochondrial myopathy, encephalopathy, lactic cidosis, and stroke-like episodes syndrome (MELAS) phenotypes] compared with age-matched healthy individuals. We found several differentially expressed genes: 35 were markedly up-regulated in the mtDNA macro-deletion group (vs. the control group) and 4 decreased; 56 genes were dysregulated in A3243G-related disorders (53 down-regulated in PEO and 3 up-regulated in MELAS). Finally, 12 genes were similarly regulated in the majority of the MEM patients under study. Amongst these, we identified an increased expression of genes related to the metabolism of the amino groups, as well as of several genes involved in genetic information processing. Moreover, few genes were similarly decreased in MEM patients vs. the control group. Real-time PCR demonstrated excellent reproducibility of the microarray-based findings. The observed expression changes are likely to represent a molecular signature for mitochondrial disorders. Furthermore, the differential expression profile of MELAS(A3243G) vs. PEO(A3243G) may support a role of nuclear background in contributing to these different clinical phenotypes. MEM microarray data are available from GEO database (http://www.ncbi.nlm.nih.gov/geo/) with the accession number: GSE1462.
authors.affiliation: Department of Neurological Science, University of Milan, Milan, Italy. marcreamy@tiscali.it
authors.forename: Marco
authors.initials: M
authors.lastname: Crimi
authors.forename: Andreina
authors.initials: A
authors.lastname: Bordoni
authors.forename: Giorgia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Laura
authors.initials: L
authors.lastname: Riva
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Sara
authors.initials: S
authors.lastname: Galbiati
authors.forename: Roberto
authors.initials: R
authors.lastname: Del Bo
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo Pietro
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004272:DNA, Mitochondrial; D012333:RNA, Messenger