Gene discovery and functional studies of mitochondrial respiratory chain disorders

Abstract

Mitochondrial respiratory chain disorders (MRCD) are one of the most challenging inborn errors of metabolism to diagnose and treat, because of their phenotypic and genetic heterogeneity, and a paucity of validated therapies. The approach opted to diagnose our MRCD patient cohort was using next generation sequencing (NGS) technology, and in particular whole exome sequencing (WES). Using our research pipeline we were able to identify novel YARS2 variants in patients with a tissue specific MRCD. Novel disease gene discoveries (CYC1 and MRPS7) causing MRCD were identified using the WES approach, and the functional studies implemented confirmed the pathogenicity of the newly identified variants. Advances in NGS technologies lead to the identification of a novel mtDNA mutation in the MT_ND3 gene and therefore rapid genetic diagnosis of a patient with Leigh disease allowing timely acceptance into a Phase 2B clinical trial. Using WES, two patients initially suspected to have a mitochondrial myopathy were diagnosed with congenital myasthenia resulting in the successful treatment for one patient. Through the research presented in this thesis, we were able to gain more knowledge about the disease mechanisms of MRCDs, and we hope that these findings will be instrumental in research towards future therapy of MRCD.