Novel mitochondrial tRNA<sup>Ile</sup>m.4282A&gt;G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype

Jackson, Christopher B.; Neuwirth, Christoph; Hahn, Dagmar; Nuoffer, Jean-Marc; Frank, Stephan; Gallati, Sabina; Schaller, André

doi:10.1136/bjophthalmol-2014-305300

Cited by 11 publications

(6 citation statements)

References 25 publications

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“…So far, disease causing D-stem variants are reported for 16 of the 22 mt-tRNA genes, and are associated with a wide range of clinical presentations (Supplementary Table 1). Some of these mt-tRNA D -stem cases have a relatively low (18-38%) muscle mutation load and clearly show phenotypical overlap with our patient, displaying relatively mild symptoms (mainly CPEO, ptosis, myopathy) with an age of onset at 26-66 years [13][14][15][16][17] . As compared to other pathogenic variants in the tRNA Met gene (summarized in [18] ) our patient has a much lower muscle heteroplasmy level, probably responsible for the milder phenotype and later onset of disease than the other reported MT-TM patients.…”

Section: Discussionsupporting

confidence: 53%

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

Hellebrekers

Blakely

Hendrickx

et al. 2019

Neuromuscular Disorders

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We report a novel mitochondrial m.4414T > C variant in the mt-tRNA Met (MT-TM) gene in an adult patient with chronic progressive external ophthalmoplegia and myopathy whose muscle biopsy revealed focal cytochrome c oxidase (COX)-deficient and ragged red fibres. The m.4414T > C variant occurs at a strongly evolutionary conserved sequence position, disturbing a canonical base pair and disrupting the secondary and tertiary structure of the mt-tRNA Met. Definitive evidence of pathogenicity is provided by clear segregation of m.4414T > C mutant levels with COX deficiency in single muscle fibres. Interestingly, the variant is present in skeletal muscle at relatively low levels (30%) and undetectable in accessible, non-muscle tissues from the patient and her asymptomatic brother, emphasizing the continuing requirement for a diagnostic muscle biopsy as the preferred tissue for mtDNA genetic investigations of mt-tRNA variants leading to mitochondrial myopathy.

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Section: Discussionsupporting

confidence: 53%

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

Hellebrekers

Blakely

Hendrickx

et al. 2019

Neuromuscular Disorders

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“…A more convenient amplicon was obtained by SspI digestion for fragment analysis on an ABI3100 capillary sequencer. Standard RFLP by inclusion of a mismatch in the primer site (Jackson et al, 2014a) was feasible, since the patient also harboured the additional polymorphism m.8610T > C and m.8614T > C resulting in a homopolymeric cytosine stretch. Therefore, an approach by fragment analysis on a capillary sequencer to discriminate the C insertion from wild type sequence was used to calculate the heteroplasmic degree.…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy

Jackson

Hahn

Schröter³

et al. 2017

European Journal of Medical Genetics

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We describe a novel frameshift mutation in the mitochondrial ATP6 gene in a 4-year-old girl associated with ataxia, microcephaly, developmental delay and intellectual disability. A heteroplasmic frameshift mutation in the MT-ATP6 gene was confirmed in the patient's skeletal muscle and blood. The mutation was not detectable in the mother's DNA extracted from blood or buccal cells. Enzymatic and oxymetric analysis of the mitochondrial respiratory system in the patients' skeletal muscle and skin fibroblasts demonstrated an isolated complex V deficiency. Native PAGE with subsequent immunoblotting for complex V revealed impaired complex V assembly and accumulation of ATPase subcomplexes. Whilst northern blotting confirmed equal presence of ATP8/6 mRNA, metabolic S-labelling of mitochondrial translation products showed a severe depletion of the ATP6 protein together with aberrant translation product accumulation. In conclusion, this novel isolated complex V defect expands the clinical and genetic spectrum of mitochondrial defects of complex V deficiency. Furthermore, this work confirms the benefit of native PAGE as an additional diagnostic method for the identification of OXPHOS defects, as the presence of complex V subcomplexes is associated with pathogenic mutations of mtDNA.

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“…Moreover, mitochondrial genome of diabetic subjects and one of three cases of hyperlipidemia, EGY7, EGY9, and EGY2 contained T16189C mutation (Table 2) associated with insulin resistance and type 2 diabetes mellitus [53,54,55,56]. Among the variants that were not related to obesity, we found that A4282G (Table 2) associated with chronic progressive external ophthalmoplegia (CPEO) was present in all samples [57]. Mutations (disease associated) EGY1 T195C, A4282G , A8108G), A10398G ,G15043A, G16129A), A16183C and T16189C EGY2 T4216C ,A4282G), A4917G), A10398A) and G15928A EGY3 T195C, A4282G , A10398G T15784C , G16390A and T16519T EGY4 T195C , A4282G , A10398G (, T15784C, G16390A and 16519 EGY5 A4282G , A10398G and G15043A EGY6 A4282G , A10398A ), T16093C and T16519T EGY7 T195C ), G3316A , A4282G, G9055A , A10398A , A11467G, A12308G , G12372A, G14831A , A16183C and T16189C EGY8 A4282G , A10398A ), C16192T and T16519T EGY9 T4216C , A4282G , A4917G , A10398A , G15928A and T16189C…”

Section: Mitochondrial Dna Analysismentioning

confidence: 87%

Complete genome sequence and analysis of nine Egyptian females with clinical information from different geographic regions in Egypt

ElHefnawi

Hegazy

Elfiky

et al. 2020

Preprint

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Egyptians are at a crossroad between Africa and Eurasia, providing useful genomic resources for analyzing both genetic and environmental factors for future personalized medicine. Two personal Egyptian whole genomes have been published previously and here nine female whole genome sequences with clinical information have been added to expand the genomic resource of Egyptian personal genomes. Here we report the analysis of whole genomes of nine Egyptian females from different regions using Illumina short-read sequencers. At 30x sequencing coverage, we identified 12 SNPs that were shared in most of the subjects associated with obesity which are concordant with their clinical diagnosis. Also, we found mtDNA mutation A4282G is common in all the samples and this is associated with chronic progressive external ophthalmoplegia (CPEO). Haplogroup and Admixture analyses revealed that most Egyptian samples are close to the other north Mediterranean, Middle Eastern, and European, respectively, possibly reflecting the into-Africa influx of human migration. In conclusion, we present wholegenome sequences of nine Egyptian females with personal clinical information that cover the diverse regions of Egypt. Although limited in sample size, the whole genomes data provides possible geno-phenotype candidate markers that are relevant to the region's diseases.

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Novel mitochondrial tRNA^Ilem.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype

Cited by 11 publications

References 25 publications

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy

Complete genome sequence and analysis of nine Egyptian females with clinical information from different geographic regions in Egypt

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Novel mitochondrial tRNAIlem.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype

Cited by 11 publications

References 25 publications

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy

Complete genome sequence and analysis of nine Egyptian females with clinical information from different geographic regions in Egypt

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Novel mitochondrial tRNA^Ilem.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype