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

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Defects in mitochondrial translation are among the most common causes of mitochondrial disease1, 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 translation2. As mammalian mitochondrial mRNAs do not have significant 5′ UTRs3, 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 homologs4, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.

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Figure 1: Compromised assembly of COX and impaired synthesis of COX subunit I in subject fibroblasts.
Figure 2: The biochemical defect in subject fibroblasts is rescued by microcell-mediated transfer of chromosome 17q.
Figure 3: Mutational analysis of TACO1 in the index subject.
Figure 4: Overexpression of TACO1 rescues the mitochondrial translation defect and the COX assembly defect in subject fibroblasts.
Figure 5: TACO1 is a mitochondrial matrix protein.
Figure 6: High levels of TACO1 or TACO1-HA expression depress mitochondrial translation in control fibroblasts.

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We acknowledge the contribution of the individuals who cared for the study subjects and the technical assistance of I. Kaus, S. Mueller-Ziermann and A. Zimmermann. We thank T. Johns for help with immunocytochemistry and the cell culture. This work was supported in part by a grant from the Canadian Institutes of Health Research to E.A.S. E.A.S. is an International Scholar of the Howard Hughes Medical Institute. R.H. is supported by the Deutsche Forschungsgemeinschaft HO 2505/2-1.

Author information

W.W. did the chromosome transfer, mutation analysis, subcellular localization and RNA immunoblotting analyses; H.A. did BN gel analyses, enzyme measurements, molecular modeling and helped write the manuscript; F.S. performed translation analyses; J.S. evaluated the index subject and affected children; B.S. evaluated the adult subjects; J.E.K. did the yeast studies; H.L. performed the linkage analysis; M.C. helped with the chromosome transfer studies; B.A.K. did the size exclusion experiments and helped with the yeast studies; R.H. performed the histological, biochemical and genetic investigation of the index subject and family members; E.A.S. designed the study and wrote the final manuscript.

Correspondence to Eric A Shoubridge.

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