Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy

doi:10.1016/0002-8703(92)90410-W

American Heart Journal

Volume 124, Issue 5, November 1992, Pages 1263-1269

https://doi.org/10.1016/0002-8703(92)90410-W Get rights and content

Abstract

Recent advances suggest that mutations in nuclear DNA are involved in the etiology of autosomal dominant hypertrophic cardiomyopathy. Mitochondria have their own DNA, and mutations in mitochondrial DNA have been shown to contribute to the genesis of various diseases. In this study, we developed rapid sequencing methods with the use of a fluorescence-based sequencing system and analyzed total mitochondrial DNA of seven patients with nonautosomal dominant hypertrophic cardiomyopathy. Multiple point mutations were observed in all patients with hypertrophic cardiomyopathy, although some of them were common among the subjects examined and the others are unique to each subject. Point mutations in transfer RNA genes were observed in five of the seven patients, and point mutations that replaced conserved amino acids were also observed. These mutations may result in the impairment of mitochondrial function. According to these results, mutations in mitochondrial DNA may contribute to the genesis of some cases of nonautosomal dominant hypertrophic cardiomyopathy, and our methods may be useful for the detection of point mutations in mitochondrial DNA.

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Complex I has an essential role in ATP production by coupling electron transfer from NADH to quinone with translocation of protons across the inner mitochondrial membrane. Isolated complex I deficiency is a frequent cause of mitochondrial inherited diseases. Complex I has also been implicated in cancer, ageing, and neurodegenerative conditions. Until recently, the understanding of complex I deficiency on the molecular level was limited due to the lack of high-resolution structures of the enzyme. However, due to developments in single particle cryo-electron microscopy (cryo-EM), recent studies have reported nearly atomic resolution maps and models of mitochondrial complex I. These structures significantly add to our understanding of complex I mechanism and assembly. The disease-causing mutations are discussed here in their structural context.
Mutational analysis of mitochondrial DNA in Brugada syndrome
2016, Cardiovascular Pathology
Brugada syndrome (BrS) is a primary electrical disease associated with an increased risk of sudden cardiac death due to ventricular fibrillation. This pathology has nuclear heterogeneous genetic origins, and at present, molecular diagnostic tests on nuclear DNA cover only 30% of BrS patients. The aim of this study was to assess the possible involvement of mitochondrial (mt) DNA variants in BrS since their etiological role in several cardiomyopathies has already been described.
The whole mt genome of BrS patients was sequenced and analyzed. A specific mtDNA mutation responsible for BrS can be excluded, but BrS patient d-loop was found to be more polymorphic than that of control cases (P= 0.003). Moreover, there appears to be an association between patients with the highest number of variants (n> 20) and four mt Single Nucleotide Polymorphism (SNPs) (T4216C, A11251G, C15452A, T16126C) and the most severe BrS phenotype (P= 0.002).
The high substitution rate found in BrS patient mtDNA is unlikely to be the primary cause of the disease, but it could represent an important cofactor in the manifestation of the BrS phenotype.
Evidence suggesting that a specific mtDNA allelic combination and a high number of mtDNA SNPs may be associated with more severe cases of BrS represents the starting point for further cohort studies aiming to test whether this mt genetic condition could be a genetic modulator of the BrS clinical phenotype.
A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with sever nephropathy
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Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia, maternal transmission and its association with a bilateral hearing impairment. Several studies reported mutations in mitochondrial genes as potentially pathogenic for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells. In the present report, we studied a Tunisian family with mitochondrial diabetes (MD) and deafness associated with nephropathy. The mutational analysis screening revealed the presence of a novel heteroplasmic mutation m.9276G>C in the mitochondrial COIII gene, detected in mtDNA extracted from leukocytes of a mother and her two daughters indicating that this mutation is maternally transmitted and suggest its implication in the observed phenotype.
Bioinformatic tools showed that m.9267G>C mutation (p.A21P) is « deleterious » and it can modify the function and the stability of the MT-COIII protein by affecting the assembly of mitochondrial COX subunits and the translocation of protons then reducing the activity of the respective OXPHOS complexes of ATP synthesis.
The nonsynonymous mutation (p.A21P) has not been reported before, it is the first mutation described in the COXIII gene which is related to insulin dependent mitochondrial diabetes and deafness and could be specific to the Tunisian population. The m.9267G>C mutation was present with a nonsynonymous inherited mitochondrial homoplasmic variation MT-COI m.5913 G>A (D4N) responsible of high blood pressure, a clinical feature detected in all explored patients.
Role of copper in regression of cardiac hypertrophy
2015, Pharmacology and Therapeutics
Citation Excerpt :
Therefore, the insufficient activation of angiogenic genes is highly responsible for the depression of coronary angiogenesis in the pathological cardiac hypertrophy. The depressed angiogenesis contributes to the impairment of the energy demand and production in the heart (Obayashi et al., 1992; Lucas et al., 2003; Fassone et al., 2011). Most of the cardiac energy requirement is met by mitochondrial oxidative phosphorylation (OxPhos) in the form of adenosine triphosphate (ATP), which is mandatory to sustain cardiac performance (Ingwall & Weiss, 2004).
Pressure overload causes an accumulation of homocysteine in the heart, which is accompanied by copper depletion through the formation of copper–homocysteine complexes and the excretion of the complexes. Copper supplementation recovers cytochrome c oxidase (CCO) activity and promotes myocardial angiogenesis, along with the regression of cardiac hypertrophy and the recovery of cardiac contractile function. Increased copper availability is responsible for the recovery of CCO activity. Copper promoted expression of angiogenesis factors including vascular endothelial growth factor (VEGF) in endothelial cells is responsible for angiogenesis. VEGF receptor-2 (VEGFR-2) is critical for hypertrophic growth of cardiomyocytes and VEGFR-1 is essential for the regression of cardiomyocyte hypertrophy. Copper, through promoting VEGF production and suppressing VEGFR-2, switches the VEGF signaling pathway from VEGFR-2-dependent to VEGFR-1-dependent, leading to the regression of cardiomyocyte hypertrophy. Copper is also required for hypoxia-inducible factor-1 (HIF-1) transcriptional activity, acting on the interaction between HIF-1 and the hypoxia responsible element and the formation of HIF-1 transcriptional complex by inhibiting the factor inhibiting HIF-1. Therefore, therapeutic targets for copper supplementation-induced regression of cardiac hypertrophy include: (1) the recovery of copper availability for CCO and other critical cellular events; (2) the activation of HIF-1 transcriptional complex leading to the promotion of angiogenesis in the endothelial cells by VEGF and other factors; (3) the activation of VEGFR-1-dependent regression signaling pathway in the cardiomyocytes; and (4) the inhibition of VEGFR-2 through post-translational regulation in the hypertrophic cardiomyocytes. Future studies should focus on target-specific delivery of copper for the development of clinical application.
Mitochondrial DNA variations associated with hypertrophic cardiomyopathy
2014, Mitochondrion
Citation Excerpt :
Both mitochondrial and nuclear gene mutations have been shown to cause HCM, either isolated or as a part of multi-organ involvement (Hagen et al., 2013). Generally, these cases are non-familial or sporadic; some follow the maternal inheritance pattern (Casali et al., 1995; Obayashi et al., 1992; Zeviani et al., 1991). Several pathogenic mtDNA mutations have been reported to be associated with HCM (Bates et al., 2012) in different populations (http://www.mitomap.org) either as an isolated phenotype or a complex syndrome.
Hypertrophic cardiomyopathy (HCM) is a primary disorder, characterized by unexplained hypertrophy of the left ventricle that frequently involved in the inter-ventricular septum. Mitochondrial DNA (mtDNA) mutations and haplogroups have been found to be associated with several diseases. Therefore, in the present study, we have sequenced the complete mtDNA of 114 clinically well-characterized HCM patients to look for the role of mtDNA variations and haplogroups in HCM phenotype among Indian patients. Complete mtDNA analysis revealed 28 novel variations, 25 disease-associated and 50 private mutations. We found 13 (11.40%) HCM patients having novel non-synonymous and/or MT-tRNA variations, of which two (m.4797C > M and m.8728T > Y) were in heteroplasmic condition. In silico prediction showed that a few mutations are pathogenic, which may affect the energy production in the heart. Unlike some of the other studies, we did not find association of mitochondrial haplogroup with HCM.
MtDNA haplogroups and osteoarthritis in different geographic populations
2014, Mitochondrion
Citation Excerpt :
As a result of the sequencing, differences in the frequency distribution of some haplogroup J-related SNPs were found between both populations (Supplementary Table 2) and, based on these results, we selected the SNP m.3394t>c for analysis because this polymorphism has also been implicated as a secondary mutation associated with LHON (Wallace, 1999). In relation to this SNP, some studies have analyzed its incidence in several diseases, like cardiac arrhythmia (Nikoskelainen et al., 1985), non-insulin dependent diabetes mellitus (Thomas et al., 1996), cardiomyopathy (Obayashi et al., 1992) or sudden infant death syndrome (Arnestad et al., 2007), all of them related with ATP deficiency; besides, this SNP has also been associated with lower O2 consumption (Matsuoka et al., 1999). These two latter characteristics, lower ATP production and lower O2 consumption, are typically related to the mtDNA haplogroup J (Marcuello et al., 2009; Martínez-Redondo et al., 2010; Mishmar et al., 2003), being the main cause of its protective effect on some degenerative and oxidative stress-related diseases (Rego-Perez et al., 2008; van der Walt et al., 2003) and its increased frequency in elderly people (Domínguez-Garrido et al., 2009; Gaweda-Walerych et al., 2008; Niemi et al., 2003).
To compare the frequency distribution of the mtDNA haplogroups in OA patients and healthy controls between the United Kingdom (UK) and Spain.
We used the single base extension (SBE) assay to obtain the European mtDNA haplogroups in 1471 OA patients and 406 healthy controls from Spain, and 453 OA patients and 280 healthy controls from the UK. Some differential haplogroup J-related single nucleotide polymorphisms (SNPs) between both populations were analyzed. The whole data was analyzed with SPSS software (v.18) following appropriate approaches that included chi-square contingency tables and logistic regression models adjusting by gender and age.
The haplogroup J appeared underrepresented in OA patients from Spain when compared with healthy controls (OR = 0.636; 95% CI: 0.444–0.911; p = 0.013). Individuals from the UK carrying the haplogroup T showed a decreased risk of OA (OR = 0.574; 95% CI: 0.350–0.939; p = 0.027). The comparison of the frequency distribution of the haplogroup J between the UK and Spain showed a decreased presence of this haplogroup in healthy controls from the UK when compared with healthy controls from Spain that is in borderline of the statistical significance (p = 0.06). The analysis of some haplogroup J-related SNPs in OA patients and healthy controls from Spain and the UK showed that the SNP m.3394t>c appeared underrepresented in the UK cohort (p = 0.038).
The proposed mitochondrial uncoupling mechanism derived from the mtDNA haplogroups J and T could be behind their protective role against OA. The different association found in Spain and the UK could reflect the adaptation of the mtDNA haplogroups to different climatic patterns. The genetic composition of the haplogroup J between the UK and Spain seems to be slightly different, being the m.3394t>c SNP one of the differentially expressed haplogroup J-related polymorphisms.

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^☆: Supported by the 1992 Young Investigator's Award of the Japanese Circulation Society.

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Point mutations in mitochondrial DNA in patients with hypertrophic cardiomyopathy☆

Abstract

Lancet

Cell

Cell

Lancet

Lancet

Am Heart J

Lancet

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochem Biophys Res Commun