A homoplasmic mitochondrial transfer Ribonucleic Acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy

Taylor, Robert W.; Giordano, Carla; Davidson, Mercy M.; d’Amati, Giulia; Bain, H H; Hayes, Christine; Leonard, H; Barron, Martin J.; Casali, Carlo; Santorelli, Filippo M.; Hirano, Michio; Lightowlers, Robert N.; DiMauro, Salvatore; Turnbull, Douglass M.

doi:10.1016/s0735-1097(03)00300-0

Cited by 158 publications

(115 citation statements)

References 29 publications

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“…15,16 Cell culture Cultured skin fibroblasts from patient 1 and her mother were maintained as previously described. 17 …”

Section: Case Reportsmentioning

confidence: 99%

“…Levels of mutant m.12261T4C and m.12264C4T mtDNA were determined by last hot cycle PCR-RFLP as previously described 17 with the modifications detailed in Table 1. Levels of mutant mtDNA were calculated as a percentage of total mtDNA.…”

Section: Last Hot Cycle Pcr Restriction Fragment Length Polymorphism mentioning

confidence: 99%

“…17 Human mt-tRNA Leu(UUR) and mt-tRNA Ser(AGY) probes were generated using the primer pairs L3200 (nucleotide positions 3200-3219) 5¢-TATACCCACACCCACCCAAG-3¢ and H3353 (3353-3334) 5¢-GCGATT AGAATGGGTACAAT-3¢, and M13-tailed L12201 (12 201-12 223) 5¢-tgtaaaa cgacggccagtTTTACCGAGAAAGCTCACAAGA-3¢ and M13-tailed H12270 (12 270-12 248) 5¢-caggaaacagctatgaccAAAGTTGAGAAAGCCATGTTGTT-3¢ (M13-tails shown in lower case), respectively. The radioactive signal of the mt-tRNA Ser(AGY) probe was normalised to that of the mt-tRNA Leu(UUR) probe for each sample and ratios were expressed relative to an age-matched control.…”

Section: High-resolution Northern Blot Analysismentioning

confidence: 99%

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Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

et al. 2012

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Although over 200 pathogenic mitochondrial DNA (mtDNA) mutations have been reported to date, determining the genetic aetiology of many cases of mitochondrial disease is still not straightforward. Here, we describe the investigations undertaken to uncover the underlying molecular defect(s) in two unrelated Caucasian patients with suspected mtDNA disease, who presented with similar symptoms of myopathy, deafness, neurodevelopmental delay, epilepsy, marked fatigue and, in one case, retinal degeneration. Histochemical and biochemical evidence of mitochondrial respiratory chain deficiency was observed in the patient muscle biopsies and both patients were discovered to harbour a novel heteroplasmic mitochondrial tRNA (mt-tRNA) Ser(AGY) (MTTS2) mutation (m.12264C4T and m.12261T4C, respectively). Clear segregation of the m.12261T4C mutation with the biochemical defect, as demonstrated by single-fibre radioactive RFLP, confirmed the pathogenicity of this novel variant in patient 2. However, unusually high levels of m.12264C4T mutation within both COX-positive (98.4 ± 1.5%) and COX-deficient (98.2 ±2.1%) fibres in patient 1 necessitated further functional investigations to prove its pathogenicity. Northern blot analysis demonstrated the detrimental effect of the m.12264C4T mutation on mt-tRNA Ser(AGY) stability, ultimately resulting in decreased steady-state levels of fully assembled complexes I and IV, as shown by blue-native polyacrylamide gel electrophoresis. Our findings expand the spectrum of pathogenic mutations associated with the MTTS2 gene and highlight MTTS2 mutations as an important cause of retinal and syndromic auditory impairment.

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“…15,16 Cell culture Cultured skin fibroblasts from patient 1 and her mother were maintained as previously described. 17 …”

Section: Case Reportsmentioning

confidence: 99%

Section: Last Hot Cycle Pcr Restriction Fragment Length Polymorphism mentioning

confidence: 99%

Section: High-resolution Northern Blot Analysismentioning

confidence: 99%

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Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

et al. 2012

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“…The first of these, an m.1835A4G heteroplasmic MTRNR2 variation, was found in a patient with a (likely unrelated) isolated complex II deficiency. Secondly, a homoplasmic m.4301A4T variation in the TRNI gene, which is next to the location for a pathogenic homoplasmic m.4300A4G mutation found in a patient with hypertrophic cardiomyopathy, 37 was observed in a severely affected female who presented with a multi-systemic profile, isolated muscle complex III deficiency, but without cardiac involvement.…”

Section: Novel Variants Of Unknown Significancementioning

confidence: 94%

Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

et al. 2012

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Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81 ± 26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup-defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients.

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“…Sporadic or inherited mutations in mitochondrial DNA (mtDNA), specifically in the mtDNA transfer ribonucleic acid (tRNA) genes, or in the nuclear genome have been associated with hypertrophic and dilated cardiomyopathy (Papadopoulou et al, 1999;Hirano et al, 2001;Bénit et al, 2003;Taylor et al, 2003). Cardiac conduction abnormalities have also been associated with different mtDNA rearrangements (Marín-García et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies

et al. 2012

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A homoplasmic mitochondrial transfer Ribonucleic Acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy

Cited by 158 publications

References 29 publications

Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies

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