Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome.
Defects in mitochondrial translation are among the most common causes of mitochondrial disease, 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. As mammalian mitochondrial mRNAs do not have significant 5' UTRs, 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, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.
Weraarpachai
Woranontee
W
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Antonicka
Hana
H
Sasarman
Florin
F
Seeger
Jürgen
J
Schrank
Bertold
B
Kolesar
Jill E
JE
Lochmüller
Hanns
H
Chevrette
Mario
M
Kaufman
Brett A
BA
Horvath
Rita
R
Shoubridge
Eric A
EA
D002886:Chromosomes, Human, Pair 17; D030401:Cytochrome-c Oxidase Deficiency / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation
D008840:Microfilament Proteins; C072061:coronin proteins; D003576:Electron Transport Complex IV