COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency

Abstract

Primary Coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by recessive mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10, a lipoidal quinone, is an essential component of the electron transport chain (ETC), shuttling electrons from complex I/II to complex III. By whole exome sequencing we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex, which contains most of CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory distress syndrome, and epileptic encephalopathy. The fifth subject had early-onset but slowly progressive clinical course, dominated by neurological deterioration with hardly any involvement of other organs. CoQ10 amount was reduced in all available specimens from mutant subjects, often associated with decrease of CoQ10-dependent ETC complex activities and reduced oxygen consumption rate in cultured cells. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model: oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expressing a human wild-type COQ4 cDNA but failed to be corrected by expressing COQ4 cDNAs with any of the nucleotide variants identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations associated with CoQ10 deficiency.