Genome-wide expression profiling of A3243G MELAS patients in quest for potential disease-modifying target genes

Abstract

Mitochondrial encephalomyopathies represent an expanding group of clinical as well as genetical heterogeneous disorders caused by mitochondrial DNA (mtDNA) mutations or nuclear gene defects. The heteroplasmic mtDNA mutation at np 3243 (3243 A>G) in the tRNALeu(UUR) gene gives rise to one of the most frequent mitochondrial diseases, the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). Affected patients present with a broad spectrum of clinical phenotypes, including features that comprise the name of the disorder such as mitochondrial encephalomyopathy, lactic acidosis and strokes, but diabetes mellitus and hearing loss can also be part of the phenotype. As the percentage of mutant genomes did not prove to be directly correlated to the course and phenotype of disease, other yet unknown factors must be involved. Recent studies have shown that eukaryotic cells are able to reconfigure their nuclear gene expression profile to accommodate various cellular processes to the functional status of mitochondria. This process might be a key to MELAS disease manifestation and could, moreover, contribute to the phenotypic variability. We used Affymetrix oligonucleotide microarrays to analyze global gene expression changes in blood samples of ten MELAS patients compared to matched controls. Acquired data were then subjected to hierarchical clustering in order to match clinical and genetical data with expression patterns. We thereby elucidated that the relative abundance of mutant mtDNA molecules is relevant for the nuclear gene expression profile. Within this context, we identified potential disease-modifying nuclear target genes and clarified how their expression correlates with the patient's profile and the clinical outcome of MELAS syndrome. In conclusion, we elucidated A3243G-related changes in blood mRNAs that distinguish MELAS patients from controls. Moreover, we demonstrated how these modifications in mRNA expression correlate with the patient's load of mutant mtDNA, clinical outcome and disease duration. Altogether, the herein presented results may provide first biomarkers for MELAS syndrome, thereby pioneering towards potential therapeutic targets.