The molecular basis of cytochrome c oxidase deficiency. (360G-Wellcome-097978_Z_11_Z)

Cytochrome c oxidase (COX) is an enzyme required for mitochondrial energy production and COX deficiency accounts for 25% of all cases of mitochondrial disease. COX deficiency may be due to a mutation in mitochondrial or nuclear subunit genes, or nuclear encoded assembly factor genes. The clinical phenotype is heterogeneous, ranging from neurodegenerative disorders to multiorgan failure. Making the diagnosis is difficult and there is no effective treatment. We will examine 45 children with iso lated COX deficiency where the genetic diagnosis is unknown. We will determine the frequency of nuclear encoded COX subunit and assembly factor gene mutations using an integrative genomics approach. We will combine targeted next generation exon sequencing of candidate genes, homozygosity mapping (in consanguineous families), whole exome sequence analysis followed by bioinformatics and functional studies. We will also investigate the effect of drug therapy in human cell cultures with confirmed ge netic COX deficiency. We expect to discover new genetic mutations in this clinically heterogeneous cohort. We will develop high throughput novel techniques which will be translated into the diagnostic laboratory. This will improve diagnosis and facilitate prenatal diagnosis in COX deficiency. Our studies using a candidate drug panel will provide insights into treatment options in COX deficiency.