Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy

Ahola, Sakari; Isohanni, Pirjo; Euro, Liliya; Brilhante, Virginia; Palotie, Aarno; Pihko, Helena; Lönnqvist, Tuula; Lehtonen, Tanita; Laine, Jukka; Tyynismaa, Henna; Suomalainen, Anu

doi:10.1212/wnl.0000000000000716

Cited by 33 publications

(31 citation statements)

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“…Very interestingly, it has recently been described an individual with low EFTs but normal EFTu levels and a clear reduction in mitochondrial translation (Supplementary Table S1). 3 This patient harbored compound heterozygous EFTs mutations c.[856C4T];[106+4A4G]. He presented ataxia, optical and peripheral neuropathy, and was also alive at the age of 21 years, but he did not show cardiomyopathy.…”

Section: Discussionmentioning

confidence: 94%

“…We also found a c.719G4C homozygous transversion in TSFM gene (OMIM *604723; NG_016971.1; GRCh38 Chr12:57,796,324; NM_005726.5) exon 6 ( Figure 1b). This exon, numbered like in Ahola et al, 3 was also amplified and resequenced using the Sanger method in both parents and a healthy sister, and the change was found heterozygous. This variant (http://databases.lovd.nl/ shared/individuals/00063251) has been previously reported only once in SNPdb (http://www.ncbi.nlm.nih.gov/projects/SNP/rs750799705, 11 September 2015) in a Galician heterozygous individual (http:// www.ciberer.es/bier/CSVS/).…”

Section: Resultsmentioning

confidence: 99%

“…3), that is conserved in 99 (63.9%) out of 155 animal species analyzed (GenBank, 11 September 2015; Supplementary Figure S1). The three-dimensional structure of the bovine elongation factor Tu (EFTu)-EFTs dimer (PDB 1XB2) 4 was obtained with the RasMol 2.6 program (http://www.rasmol.org).…”

Section: Resultsmentioning

confidence: 99%

“…3,10 Seven patients from five different pedigrees harbored, in homozygosity, a EFTs (p.(Arg312Trp)) amino acid substitution. Despite pulse labeling of mitochondrial translation products only revealed a moderate reduction in mitochondrial protein synthesis, all of these patients died of encephalomyopathy, hypertrophic cardiomyopathy or liver failure before the age of 2 months.…”

Section: Discussionmentioning

confidence: 99%

“…He presented ataxia, optical and peripheral neuropathy, and was also alive at the age of 21 years, but he did not show cardiomyopathy. 3 In a different pedigree, two sisters harbored (p.(Cys315Tyr))/ (p.(Gln286Ter)) mutations, suffered from hypertrophic cardiomyopathy and survived for 415 years. These patients had low levels of both EFTs and EFTu, but mitochondrial translation was partially decreased in one of them and unaffected in the other one.…”

Section: Discussionmentioning

confidence: 99%

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Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy

et al. 2016

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Oxidative phosphorylation dysfunction has been found in many different disorders. This biochemical pathway depends on mitochondrial protein synthesis. Thus, mutations in components of the mitochondrial translation system can be responsible for some of these pathologies. We identified a new homozygous missense mutation in the mitochondrial translation elongation factor Ts gene in a patient suffering from slowly progressive childhood ataxia and hypertrophic cardiomyopathy. Using cell, biochemical and molecular-genetic protocols, we confirm it as the etiologic factor of this phenotype. Moreover, as an important functional confirmation, we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts. Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy

et al. 2016

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A novel composition of two heterozygous GFM1 mutations in a Chinese child with epilepsy and mental retardation

You

Qiu

et al. 2020

Brain and Behavior

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Mitochondria are the energy factories of eukaryotic cells, which contain thousands of proteins that maintain their specific functions. These proteins are encoded by mitochondrial DNA and the nuclear genome. Pathogenic mutations in these mitochondrial genes can cause multiple serious diseases (Scheffer et al., 2017; Thompson et al., 2020). Mitochondrial DNA encodes its own mRNA, rRNA, and tRNA, to synthesize some of the proteins it needs. Proteins encoded by mitochondrial DNA are involved in the composition of oxidative phosphorylation system complexes, so any gene mutation that affects the replication, transcription, and translation of mitochondrial DNA may cause oxidative phosphorylation deficiency (de Laat, Rodenburg, & Smeitink, 2014). Mitochondrial translation is crucial for maintaining

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Novel Mutation in the TSFM Gene Causes an Early‐Onset Complex Chorea without Basal Ganglia Lesions

Riesen

Biskup

Kühn

et al. 2021

Movement Disord Clin Pract

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Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy

Abstract: We show that in addition to early-onset cardiomyopathy, TSFM mutations should be considered in childhood and juvenile encephalopathies with optic and/or peripheral neuropathy, ataxia, or Leigh disease.

Cited by 33 publications

References 42 publications

Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy

Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy

A novel composition of two heterozygous GFM1 mutations in a Chinese child with epilepsy and mental retardation

Novel Mutation in the TSFM Gene Causes an Early‐Onset Complex Chorea without Basal Ganglia Lesions

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