Submission Details

The relationship between MT-TS2 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 5, 2022. The MT-TS2 gene encodes one of two mitochondrial transfer RNAs (tRNAs) for serine (AGU/C). 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, resulting in impaired OXPHOS enzyme activities.

MT-TS2 was first reported in relation to maternally-inherited primary mitochondrial disease in 1998 in a mother and daughter who were both affected with bilateral cataracts, hearing loss, and diabetes (PMID: 9792552). While various names could be given to the constellation of features seen in those with MT-TS2-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MT-TS2 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting the gene-disease relationship between MT-TS2 and primary mitochondrial disease includes case-level data and experimental data. This curation includes five variants (m.12207G>A, m.12258C>A, m.12261T>C, m.12262C>A, m.12264C>T) observed in seven probands in six publications (PMIDs: 9792552, 10090882, 16950817, 21257182, 22369973, 22378285). Affected individuals had varying clinical features including cataracts, retinal dystrophy, hearing loss, myopathy, ataxia, seizures, global developmental delay, diabetes, Wolff-Parkinson-White arrhythmia, hypertrophic cardiomyopathy, and hypogonadotropic hypogonadism. Labs revealed elevated blood lactate and elevated creatine kinase. Muscle biopsy, when performed, generally showed reduced activities of complexes I, I+III, III, and/or IV. Brain imaging was normal in some cases. In one individual brain imaging revealed changes in the basal ganglia and diffuse atrophy with an enlarged cisterna magna and in another showed changes in the cerebral white matter. Heteroplasmy levels were variable – some individuals had the highest levels in muscle with the variant being undetectable in other tissues while others had the variant present at homoplasmy in multiple tissues. Northern blotting and single fiber testing further supported variant pathogenicity for case-level scoring (PMIDs: 22378285, 21257182, 9792552). The mechanism of pathogenicity appears to be loss of function due to altered RNA secondary structure. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease and in vitro assays demonstrating altered function in non-patient cells as a result of variants in MT-TS2 (PMID: 16671096, 33340416).

In summary, there is moderate evidence to support the relationship between MT-TS2 and maternally-inherited primary mitochondrial disease. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 5, 2022 (SOP Version 9).