Téléthon Belge - PROJET 2011: Molecular diagnosis in isolated Complex I deficiency in patients.

Mitochondria are the energy providing system of the cell. This process, referred to as oxidative phosphorylation (OXPHOS) or the respiratory chain, is controlled ot the genetic level by two genomes : the mitochondrial and the nuclear genome. A disruption of the OXPHOS system, which consists of five large multimeric enzyme complexes, results in life threatening diseases. These mitochondrial cytopathies are a heterogeneous group of disorders with an onset at any age and, very often, a multisystem involvement with a particular preference for energy demanding organs and tissues.
The diagnosis of a mitochondrial disorder at the molecular level is challenging given the very large number of genes that are involved. Over the last 20 years, numerous alterations in both the mitochondrial and nuclear DNA have been reported to cause mitochondrial diseases. However, in spite of major research efforts with Sanger sequencing technology, the majority of patients remains undiagnosed at the molecular level. Today, next generation sequencing technology (NGS) offers the opportunity through whole exome (parallel) sequencing to identify the molecular defect at gene level in a single patient. We aim to investigate a cohort of 20 patients with a well-documented isolated complex I impairment. This strategy of a joint clinical, biochemical and genetic approach will not only allow to identify the disease causing mutations in these families, but also to expand the current gene portfolio of mitochondrial disease. Knowledge of the underlying gene defect is essential to patient management, disease prognosis, prevention and family planning. Eventually, our results will help to elucidate the mechanisms of mitochondrial disorder in general.