The relationship between MT-TK and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of May 17, 2021. The MT-TK gene encodes the mitochondrial transfer RNA (tRNA) for lysine. Defects of this tRNA lead to impaired mitochondrial translation, which leads to decreased synthesis of mtDNA-encoded subunits of oxidative phosphorylation (OXPHOS) complexes I, III, IV, and V and thus impaired OXPHOS enzyme activities.
The MT-TK gene was first reported in relation to maternally inherited Leigh syndrome spectrum in 1993 (PMID: 8170567). Of note, variants (particularly m.8344A>G) in MT-TK are more commonly associated with other mitochondrial disease clinical syndromes, especially MERRF (myoclonus epilepsy, ragged red fibers). Evidence supporting the gene-disease relationship between MT-TK and Leigh syndrome spectrum includes case-level data and experimental data. This curation included 2 variants in 15 cases (11 with m.8344A>G and 4 with m.8363G>A) from 13 publications (PMIDs: 24374964, 18319067, 10868777, 22981260, 18176892, 8602753, 33718511, 9851442, 30271374, 11108511, 8170567, 8133313, 12661941). Of note, while Gene Curation SOP Version 8 maxes case level missense variant total score at 7, the Mitochondrial Disease Gene Curation Expert Panel agreed the maximum score would be 12 given that the majority of pathogenic mitochondrial DNA variants are missense variants (the total score for genetic level evidence in this curation was 11). Segregation information is scored as case level evidence according to the criteria established by the Mitochondrial Disease Gene Curation Expert Panel. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and functional alteration in non-patient cells (PMIDs: 27977873, 7739567, 22354625).
In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 17, 2021 (SOP Version 8).
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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