Mitochondrial diseases, caused by dysfunction of the respiratory chain are characterised by very high clinical as well as genetic heterogeneity. In most of the cases multiple organs and systems are involved with special place taken by muscular and nervous systems due to their high respiratory requirements. From the genetic point of view mitochondrial diseases are exceptionally difficult to study. As the respiratory chain function is secured by the cooperation of up to 1500 proteins, the number of genes in which mutations may lead to OXPHOS dysfunction may be close to that number. Another difficulty is that the respiratory chain subunits are encoded by two different genomes. 13 of them are localised in mitochondrial DNA (mtDNA) – small, multicopy maternally inherited molecule. The remaining 70 are nuclear encoded. This means that the mutations responsible for mitochondrial diseases may be inherited both in a mendelian and a maternal way. A group of the diseases caused by mutations in nuclear genes encoding proteins responsible for mtDNA maintenance is worth mentioning. mtDNA depletion or multiple deletions are observed as a result of such mutations. POLG and C10orf2 mutations are the most frequent in Polish patients. Next generation sequencing (NGS) enabled detailed analysis of both genomes. The application of NGS to mtDNA analysis in our hands has proven to be an effective tool to capture known as well as novel pathogenic variants. Due to the high number of reads and high coverage it also allows the detection of low levels of heteroplasmy. WES was applied to analyse genetic background of the disease in adult patients with progressive external ophthalmoplegia, multiple mtDNA deletions and negative screening for POLG and C10orf2 mutations. The preliminary results indicate that the success ratio is much lower than in paediatric patients. FINANCIAL SUPPORT: This work was supported by the National Science Center of Poland grant 2014/15/B/ NZ2/02272.
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