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TSFM encodes the mitochondrial translation elongation factor Ts (EFTs), critical for organellar protein synthesis. Biallelic TSFM dysfunction has been linked to a recessive, infantile‐onset multisystem disorder that includes Leigh syndrome ([PMID:25037205]).
In a cohort of three affected individuals from two unrelated families, juvenile‐onset Leigh syndrome was accompanied by optic atrophy, ataxia, and peripheral neuropathy under an autosomal recessive inheritance model ([PMID:25037205]). All patients harbored compound heterozygous TSFM variants with complete segregation in sibships, consistent with AR transmission.
The variant spectrum comprises missense and nonsense alleles, notably c.944G>A (p.Cys315Tyr) and c.856C>T (p.Gln286Ter) in one sib‐pair, and c.856C>T combined with an intronic splice‐site change in a second family. None of these alleles were observed as homozygotes in 35,000 Finnish controls, implying embryonic or early lethality of null genotypes ([PMID:25037205]).
Functional studies in patient fibroblasts demonstrated marked instability and marked depletion of EFTs, resulting in a pronounced mitochondrial translation defect. Molecular modeling predicted disruption of protein folding and interaction with EF‐Tu, corroborated by biochemical assays showing absent EFTs activity ([PMID:25037205]).
No conflicting evidence has been reported to date. The phenotype spectrum extends beyond cardiomyopathy to include classic Leigh‐style neuropathology, reinforcing TSFM’s role in mitochondrial encephalopathies.
Overall, TSFM shows a strong gene–disease association for autosomal recessive Leigh syndrome, supported by three probands in two families, clear segregation, and concordant functional data. TSFM mutation analysis should be integrated into diagnostic panels for pediatric and juvenile Leigh‐like encephalopathies with optic atrophy, neuropathy, or ataxia. Key take‐home: TSFM biallelic variants cause a recessive form of Leigh syndrome with neurologic and ophthalmologic manifestations.
Gene–Disease AssociationStrong3 probands across 2 families, segregation in sibships and concordant functional data Genetic EvidenceStrong3 AR probands with compound heterozygous LoF/missense variants and segregation in two families Functional EvidenceModeratePatient fibroblast assays and molecular modeling confirm EFTs instability and mitochondrial translation defect |