Point mutations in mitochondrial DNA of patients with hypertrophic cardiomyopathy

Obayashi, Toshihiro; Takasawa, Masaaki; Hattori, Kazuki; Tanaka, Masashi; Sugiyama, Satoru; Itō, Takayuki; Ozawa, Takayuki

doi:10.1016/0022-2828(92)90675-p

Cited by 10 publications

(16 citation statements)

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“…Therefore, the ratio of the intercept of the vertical axis of the deleted mtDNA line to the intercept of the vertical axis of the normal mtDNA line gave the proportion of deleted mtDNA (2%) to normal mtDNA before amplification. Based on the data obtained from 4 cases (#20, 21,23,25), the proportion of deleted mtDNA to normal mtDNA was determined to be 0´3±2´0%.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, the sequence of mutant mtDNA predicts a 7´5 kDa abnormal protein that is composed of 41 amino acid residues from the Nterminal side of the ATPase subunit 6 and 25 amino acid residues from the sequence of the D-loop region. The truncated protein did not include ND 3±6 of complex I, cyt b of the subunit of complex III, COIII in the subunit of complex IV and ATPase6 in the subunit of complex V [25]. It is possible that this mutant protein disturbs the molecular assembly of the energy-transducting complexes, subsequently failing to transduce redox energy into the driving force for ATP synthesis due to the dysfunction of the electron transfer chain, resulting in the abnormal extent to the ATP and ADP metabolism i.e.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial DNA deletion associated with the reduction of adenine nucleotides in human atrium and atrial fibrillation

Tsuboi

Hisatome

Morisaki

et al. 2001

Eur J Clin Investigation

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA deletion associated with the reduction of adenine nucleotides in human atrium and atrial fibrillation

Tsuboi

Hisatome

Morisaki

et al. 2001

Eur J Clin Investigation

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“…One, p.C93Y, was inherited digenically with a sarcomeric mutation, a phenomenon only rarely observed (Arbustini et al 1998). Interestingly, many of the rare variants we identified were unlikely to be associated with any structural effect including two variants, m.15452C>A, p.L236I and m.14927A>G, p.T61A, that have been previously reported as being associated with CIII dysfunction (Marin-Garcia and Goldenthal 1997) and cardiomyopathy (Obayashi et al 1992;Marin-Garcia et al 2000;Casademont and Miro 2002). m.15452C>A is a frequently occurring variant (~4.3%) and both amino acids are weakly conserved (Fig.…”

Section: Discussionmentioning

confidence: 61%

MT‐CYB mutations in hypertrophic cardiomyopathy

Hagen

Aidt

Havndrup

et al. 2013

Molec Gen & Gen Med

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Mitochondrial dysfunction is a characteristic of heart failure. Mutations in mitochondrial DNA, particularly in MT-CYB coding for cytochrome B in complex III (CIII), have been associated with isolated hypertrophic cardiomyopathy (HCM). We hypothesized that MT-CYB mutations might play an important causal or modifying role in HCM. The MT-CYB gene was sequenced from DNA isolated from blood from 91 Danish HCM probands. Nonsynonymous variants were analyzed by bioinformatics, molecular modeling and simulation. Two germline-inherited, putative disease-causing, nonsynonymous variants: m.15024G>A; p.C93Y and m.15482T>C; p.S246P were identified. Modeling showed that the p.C93Y mutation leads to disruption of the tertiary structure of Cytb by helix displacement, interfering with protein–heme interaction. The p.S246P mutation induces a diproline structure, which alters local secondary structure and induces a kink in the protein backbone, interfering with macromolecular interactions. These molecular effects are compatible with a leaky phenotype, that is, limited but progressive mitochondrial dysfunction. In conclusion, we find that rare, putative leaky mtDNA variants in MT-CYB can be identified in a cohort of HCM patients. We propose that further patients with HCM should be examined for mutations in MT-CYB in order to clarify the role of these variants.

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“…1) and consensually considered a polymorphism, reported as associated to haplogroup U5, present in European populations (Herrnstadt et al 2002), this assumption may not be true for the nucleotide change at position 3338. This modification was found by sequencing analysis only in one hypertrophic cardiomyopathy patient (Obayashi et al 1992;Ozawa et al 1991), in one multiple sclerosis control subject (Chalmers et al 1995), in one Parkinson's patient and in our Alzheimer's patient (Grazina et al 2005). Meanwhile, an absence of Rsa I cleavage site was found in several samples at nucleotide 3337 (Macaulay et al 1999).…”

Section: Mitochondrial Dna Mutations and Risk For Admentioning

confidence: 73%

Genetic basis of Alzheimer's dementia: role of mtDNA mutations

Grazina

Pratas

Silva

et al. 2006

Genes Brain and Behavior

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Alzheimer's disease (AD) is the most common neurodegenerative disorder associated to dementia in late adulthood. Amyloid precursor protein, presenilin 1 and presenilin 2 genes have been identified as causative genes for familial AD, whereas apolipoprotein E epsilon4 allele has been associated to the risk for late onset AD. However, mutations on these genes do not explain the majority of cases. Mitochondrial respiratory chain (MRC) impairment has been detected in brain, muscle, fibroblasts and platelets of Alzheimer's patients, indicating a possible involvement of mitochondrial DNA (mtDNA) in the aetiology of the disease. Several reports have identified mtDNA mutations in Alzheimer's patients, suggesting the existence of related causal factors probably of mtDNA origin, thus pointing to the involvement of mtDNA in the risk contributing to dementia, but there is no consensual opinion in finding the cause for impairment. However, mtDNA mutations might modify age of onset, contributing to the neurodegenerative process, probably due to an impairment of MRC and/or translation mechanisms.

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Point mutations in mitochondrial DNA of patients with hypertrophic cardiomyopathy

Cited by 10 publications

References 0 publications

Mitochondrial DNA deletion associated with the reduction of adenine nucleotides in human atrium and atrial fibrillation

Mitochondrial DNA deletion associated with the reduction of adenine nucleotides in human atrium and atrial fibrillation

MT‐CYB mutations in hypertrophic cardiomyopathy

Genetic basis of Alzheimer's dementia: role of mtDNA mutations

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