The relationship between TACO1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 29, 2024. TACO1 encodes the translational activator of cytochrome c oxidase I protein, which is required for translation of the cytochrome c oxidase subunit I (COX I), a component of complex IV of the mitochondrial respiratory chain.
TACO1 was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19503089). While various names have been given to the constellation of features seen in those with TACO1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the TACO1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, TACO1 was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP V6), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the two probands included in the LSS curation.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four frameshift or termination variants in five probands from four publications (PMIDs: 19503089, 25044680, 32444556, 33709035). Age of onset ranges from childhood to adulthood and all reported cases appear to be living at the time of report. Clinical features include typically childhood onset motor regression, cognitive decline, dystonia, muscle weakness, optic atrophy, and sensorimotor peripheral neuropathy. Muscle biopsies showed complex IV deficiency and COX-negative fibers. Brain imaging was consistent with leukoencephalopathy and/or LSS.
The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of TACO1, functional alteration in patient cells, rescue in patient cells, and a mouse model (PMIDs: 33709035, 19503089, 27319982).
In summary, there is definitive evidence to support the relationship between TACO1 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 29, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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