Journal Article

Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome

Chevrette, Mario, Antonicka, Hana, Schrank, Bertold, Kaufman, Brett A, Shoubridge, Eric A, Sasarman, Florin, Seeger, Jürgen, Weraarpachai, Woranontee, Kolesar, Jill E, Lochmüller, Hanns, Horvath, Rita

2009

Overview

Eric Shoubridge and colleagues report the identification of a mutation in the CCDC44 gene that is causal in a Leigh syndrome pedigree. The CCDC44 gene product, TACO1, is involved in mitochondrial translation and is the first specific mitochondrial translational activator identified in mammals. Defects in mitochondrial translation are among the most common causes of mitochondrial disease 1 , but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast Saccharomyces cerevisiae , all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5′ UTRs and mediate translation 2 . As mammalian mitochondrial mRNAs do not have significant 5′ UTRs 3 , alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44 , encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable degree of structural similarity with bacterial homologs 4 , and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Amino acids / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Chromosomes, Human, Pair 17 / Crystal structure / Cytochrome / Cytochrome oxidase / Cytochrome-c Oxidase Deficiency - genetics / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Electron Transport Complex IV - genetics / Electron Transport Complex IV - metabolism / Errors of metabolism / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Genome-Wide Association Study / Health aspects / Human Genetics / Humans / Leigh disease / Leigh Disease - genetics / letter / Mammals / Medical research / Medical sciences / Metabolic diseases / Microfilament Proteins - genetics / Microsatellite Repeats / Miscellaneous hereditary metabolic disorders / Mitochondrial DNA / Molecular weight / Mutation / Neurology / Physiological aspects / Proteins / Risk factors / Saccharomyces cerevisiae / Yeasts