The relationship between MT-TL2 and Leigh syndrome spectrum (LSS) was evaluated using the ClinGen Clinical Validity Framework as of April 14, 2021. The MT-TL2 gene encodes the mitochondrial transfer RNA (tRNA) for leucine (CUN). 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-TL2 gene has been associated with chronic progressive external ophthalmoplegia (CPEO) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). However, after extensive literature review, while the reported cases have brain appearances similar to those observed in LSS, evidence of variant pathogenicity was insufficient. Additionally, there is no experimental evidence to support this gene-disease relationship.
In summary, there is no evidence for a causal role for MT-TL2 variants in maternally-inherited LSS. This gene-disease association is not supported by experimental evidence and no reports have directly implicated the gene in LSS.
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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