Discovery of the new genes in mitochondrial disorders Identification of new genes responsible for mitochondrial disorders and further functional characterization of the corresponding proteins by using several techniques including the analysis of transcription profile
Mitochondrial disorders can be due to defects of either mtDNA or nuclear DNA genes. The latter can encode structural components of the five respiratory chain complexes, or factors controlling their expression, assembly, function and turnover. In spite of the recent discovery of several nuclear disease genes associated with mitochondrial disorders, the molecular and cellular pathogenesis of most of them is still unknown. We propose to apply the microarray technology to characterize the genes and molecular pathways involved in the pathogenesis of some defects of oxidative phosphorylation (OXPHOS).
In particular, we want to answer the following questions.
(1) Is there a consistent pattern of expression of individual genes, or sets of genes belonging to the same metabolic pathway(s), in patients harboring the same genetic defect affecting OXPHOS?
(2) Is there a consistent pattern of expression of genes in patients affected by a similar biochemical defect due to different causes (e.g. mutations in nuclear or in mitochondrially encoded genes)?
(3) Is there a consistent pattern of expression of genes in patients affected by different biochemical defects of the mitochondrial energy metabolism resulting in the same clinical phenotype?
Data from cell lines and tissue biopsy specimens of the patients with mitochondrial disease and CI, CIV and combined CI plus IV deficiency will be tested on GeneCHIPs using the Affymetrix platform. Affymetrix is chosen as it allows the analysis of the whole transcriptome and the construction of databases as every sample is individually analysed and compared with any other sample. The first objective is to identify discriminative signatures between patients and controls and between patients with a knowingly different genetic cause or biochemical abnormality. The second objective is to identify pathogenic processes, which requires an in-depth analysis, including all currently available biological information. A similar approach has been successfully applied in determining specific gene expression profiles in metastasis of human tumours, by comparing data on solid tumours of diverse types. The same rationale is applied for this project, in which a broad variety of patient’s samples are being tested to identify overlapping gene expression difference in genes or groups of related genes, which may represent core processes in OXPHOS pathology.
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