CPEO associated with a single nucleotide deletion in the mitochondrial tRNA
            <sup>Tyr</sup>
            gene

Raffelsberger, Thomas; Rossmanith, Walter; Thaller-Antlanger, H.; Bittner, Reginald E.

doi:10.1212/wnl.57.12.2298

Cited by 24 publications

(17 citation statements)

References 9 publications

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“…Notice that gene mutation A5843G, previously annotated C55 in mt-tRNA Tyr , is considered in this work as C54 according to the mt-tRNA database numbering from Pütz et al (2007). A fourth pathogenic mutant was not considered in this work since it concerns a nucleotide deletion in the acceptor stem (Raffelsberger et al 2001). (B) Interaction model of human mt-TyrRS with tRNA.…”

Section: Tyrmentioning

confidence: 99%

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNA^Tyr is associated with structural perturbations in tRNA architecture

Bonnefond¹,

Florentz²,

Giegé³

et al. 2008

RNA

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A growing number of human pathologies are ascribed to mutations in mitochondrial tRNA genes. Here, we report biochemical investigations on three mt-tRNA Tyr molecules with point substitutions associated with diseases. The mutations occur in the atypical T-and D-loops at positions homologous to those involved in the tertiary interaction network of canonical tRNAs. They do not correspond to tyrosine identity positions and likely do not contact the mitochondrial tyrosyl-tRNA synthetase during the aminoacylation process. The impact of these substitutions on mt-tRNA Tyr tyrosylation and structure was investigated using the corresponding tRNA transcripts. In vitro tyrosylation efficiency is decreased 600-fold for mutant A22G (mitochondrial gene mutation T5874C), 40-fold for G15A (C5877T), and is without significant effect on U54C (A5843G). Comparative solution probings with lead and nucleases on mutant and wild-type tRNA Tyr molecules reveal a greater sensitivity to single-strand specific probes for mutants G15A and A22G. For both transcripts, the mutation triggers a structural destabilization in the D-loop that propagates toward the anticodon arm and thus hinders efficient tyrosylation. Further probing analysis combined with phylogenetic data support the participation of G15 and A22 in the tertiary network of human mt-tRNA Tyr via nonclassical Watson-Crick G15-C48 and G13-A22 pairings. In contrast, the pathogenic effect of the tyrosylable mutant U54C, where structure is only marginally affected, has to be sought at another level of the tRNA Tyr life cycle.

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Section: Tyrmentioning

confidence: 99%

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNA^Tyr is associated with structural perturbations in tRNA architecture

Bonnefond¹,

Florentz²,

Giegé³

et al. 2008

RNA

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“…'PEO plus' patients have involvement of other organs as well [1] . Molecular etiologies of PEO include mitochondrial DNA (mtDNA) rearrangements such as large-scale deletions [2][3][4] and mutations in mitochondrial tRNA genes [5][6][7] . Several nuclear gene defects may result in multiple mtDNA deletions and PEO with an autosomal dominant [8] or autosomal recessive [9] mode of inheritance.…”

Section: Introductionmentioning

confidence: 99%

Progressive External Ophthalmoplegia in Southwestern Finland: A Clinical and Genetic Study

Martikainen

Hinttala

Röyttä³

et al. 2012

Neuroepidemiology

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Background: Progressive external ophthalmoplegia (PEO) is a common phenotype of mitochondrial disease. Molecu- lar etiologies include sporadic, large-scale deletions in mitochondrial DNA (mtDNA), multiple mtDNA deletions secondary to autosomal dominant or recessive mutations and mtDNA point mutations. Methods: We studied the prevalence and clinical and genetic characteristics of PEO in a defined population in southwestern Finland. A total of 620 patients were first identified from the patient registry at the Turku University Hospital over an 18-year period. The medical records of these patients were scrutinized, and those with clinical features compatible with PEO were ascertained. Results: We identified 10 patients with possible PEO. The patients were examined clinically, and DNA was analyzed for mtDNA deletions and for the m.3243A>G and m.8344A>G mtDNA point mutations. The ANT1, PEO1, POLG1 and POLG2 genes were sequenced. We confirmed the clinical diagnosis of PEO in 6 patients. Large-scale mtDNA deletions were detected in 3 out of 6 PEO patients and mutations in the POLG1 gene in 1 out of 6. We did not find any mutations in the ANT1, PEO1 or POLG2 genes. Conclusions: Our results suggest that molecular investigation of patients with PEO, either sporadic or familial, should start with an analysis for mtDNA deletions, followed by an analysis of the POLG1 gene.

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“…In most sporadic cases (60%) CPEO is due to large scale deletions of mitochondrial DNA (mtDNA). Cases with duplications, single nucleotide deletion and point mutations have also been described [1,2]. Large scale rearrangements are usually sporadic, point tRNA mutations often maternally inherited [3].…”

Section: Introductionmentioning

confidence: 99%

Chronic progressive external ophthalmoplegia: A new heteroplasmic tRNALeu(CUN) mutation of mitochondrial DNA

Cardaioli

Pozzo

Malfatti

et al. 2008

Journal of the Neurological Sciences

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CPEO associated with a single nucleotide deletion in the mitochondrial tRNA ^Tyr gene

Cited by 24 publications

References 9 publications

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNA^Tyr is associated with structural perturbations in tRNA architecture

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNA^Tyr is associated with structural perturbations in tRNA architecture

Progressive External Ophthalmoplegia in Southwestern Finland: A Clinical and Genetic Study

Chronic progressive external ophthalmoplegia: A new heteroplasmic tRNALeu(CUN) mutation of mitochondrial DNA

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CPEO associated with a single nucleotide deletion in the mitochondrial tRNA Tyr gene

Cited by 24 publications

References 9 publications

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNATyr is associated with structural perturbations in tRNA architecture

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNATyr is associated with structural perturbations in tRNA architecture

Progressive External Ophthalmoplegia in Southwestern Finland: A Clinical and Genetic Study

Chronic progressive external ophthalmoplegia: A new heteroplasmic tRNALeu(CUN) mutation of mitochondrial DNA

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CPEO associated with a single nucleotide deletion in the mitochondrial tRNA ^Tyr gene

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNA^Tyr is associated with structural perturbations in tRNA architecture

Decreased aminoacylation in pathology-related mutants of mitochondrial tRNA^Tyr is associated with structural perturbations in tRNA architecture