A novel homoplasmic mutation in mtDNA with a single evolutionary origin as a risk factor for cardiomyopathy.
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ABSTRACT:
SUBMITTER: Shin WS
PROVIDER: S-EPMC1287941 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients.ResultsHere we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of the m.13094 T > C heteroplasmic mutation and also increases the mitochondrial DNA levels of the m.11778G > A mitochondrial genotype.ConclusionsThese results suggest that ketogenic diet could be a therapeutic strategy for Leber hereditary optic neuropathy.
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Project description:Asian rice, Oryza sativa, is one of world's oldest and most important crop species. Rice is believed to have been domesticated ∼9,000 y ago, although debate on its origin remains contentious. A single-origin model suggests that two main subspecies of Asian rice, indica and japonica, were domesticated from the wild rice O. rufipogon. In contrast, the multiple independent domestication model proposes that these two major rice types were domesticated separately and in different parts of the species range of wild rice. This latter view has gained much support from the observation of strong genetic differentiation between indica and japonica as well as several phylogenetic studies of rice domestication. We reexamine the evolutionary history of domesticated rice by resequencing 630 gene fragments on chromosomes 8, 10, and 12 from a diverse set of wild and domesticated rice accessions. Using patterns of SNPs, we identify 20 putative selective sweeps on these chromosomes in cultivated rice. Demographic modeling based on these SNP data and a diffusion-based approach provide the strongest support for a single domestication origin of rice. Bayesian phylogenetic analyses implementing the multispecies coalescent and using previously published phylogenetic sequence datasets also point to a single origin of Asian domesticated rice. Finally, we date the origin of domestication at ∼8,200-13,500 y ago, depending on the molecular clock estimate that is used, which is consistent with known archaeological data that suggests rice was first cultivated at around this time in the Yangtze Valley of China.
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Project description:The presence of a genetic component in longevity is well known. Here, the association of a mtDNA mutation with a prolonged life span in humans was investigated. Large-scale screening of the mtDNA main control region in leukocytes from subjects of an Italian population revealed a homoplasmic C150T transition near an origin of heavy mtDNA-strand synthesis in approximately 17% of 52 subjects 99-106 years old, but, in contrast, in only 3.4% of 117 younger individuals (P = 0.0035). Evidence was obtained for the contribution of somatic events, under probable nuclear genetic control, to the striking selective accumulation of the mutation in centenarians. In another study, among leukocyte mtDNA samples from 20 monozygotic and 18 dizygotic twins, 60-75 years old, 30% (P = 0.0007) and 22% (P = 0.011), respectively, of the individuals involved exhibited the homoplasmic C150T mutation. In a different system, i.e., in five human fibroblast longitudinal studies, convincing evidence for the aging-related somatic expansion of the C150T mutation, up to homoplasmy, was obtained. Most significantly, 5' end analysis of nascent heavy mtDNA strands consistently revealed a new replication origin at position 149, substituting for that at 151, only in C150T mutation-carrying samples of fibroblasts or immortalized lymphocytes. Considering the aging-related health risks that the centenarians have survived and the developmental risks of twin gestations, it is proposed that selection for a remodeled replication origin, inherited or somatically acquired, provides a survival advantage and underlies the observed high incidence of the C150T mutation in centenarians and twins.
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Project description:It is generally accepted that patients with chronic progressive ophthalmoplegia caused by single large-scale deletion (SLD) of mitochondrial DNA (mtDNA) only harbor mutation in skeletal and eye muscles. The aim of this study was to investigate the presence and the level of heteroplasmy of mtDNA deletions in mitotic tissues of patients displaying mtDNA deletion of mitotic tissues in patients with SLDs and pure muscle phenotype. MtDNA mutation load was studied in three mitotic (urine epithelial cells, buccal mucosa, and blood) and one postmitotic (skeletal muscle) tissues in 17 patients with SLDs of mtDNA and pure muscle involvement. All patients had mtDNA deletion in skeletal muscle, and 78% of the patients also displayed the mtDNA deletion in mitotic tissues. The mtDNA mutation load was higher in skeletal muscle versus mitotic tissues. The mtDNA mutation load did not correlate with age of sampling of tissues, but there was a correlation between the mtDNA mutations load in skeletal muscle and (1) the site of 5' end breaking point of the SLD, (2) the size of SLD, (3) the number of affected tRNAs, and (4) age at onset (r > 0.58, P < 0.05). The findings indicate that mtDNA mutation in mitotic tissue is common in patients with SLDs of mtDNA. The lack of correlation between age of tissue sampling, age at onset, and mtDNA mutation load in mitotic tissues indicates that there is no extensive post-natal modification of mtDNA mutation load in mitotic tissues of patients with pure muscle phenotype.
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Project description:Heat shock protein 20 (Hsp20) has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peripartum cardiomyopathy. Previous findings showed that cardiac-specific overexpression of this mutant were associated with reduced autophagy, left ventricular dysfunction and early death in male mice. However, this study indicates that females have normal function with no alterations in autophagy but died within a week after 1-4 pregnancies. Further examination of mutant females revealed left ventricular chamber dilation and hypertrophic remodelling. Echocardiography demonstrated increases in left ventricular end-systolic volume and left ventricular end-diastolic volume, while ejection fraction and fractional shortening were depressed following pregnancy. Subsequent studies revealed that cardiomyocyte apoptosis was elevated in mutant female hearts after the third delivery, associated with decreases in the levels of Bcl-2/Bax and Akt phosphorylation. These results indicate that the human S10F mutant is associated with dysregulation of cell survival signalling, accelerated heart failure and early death post-partum.
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Project description:Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy characterized by impaired diastolic ventricular function resulting in a poor clinical prognosis. Rarely, heritable forms of RCM have been reported, and mutations underlying RCM have been identified in genes that govern the contractile function of the cardiomyocytes. We evaluated 8 family members across 4 generations by history, physical examination, electrocardiography, and echocardiography. Affected individuals presented with a pleitropic syndrome of progressive RCM, atrioventricular septal defects, and a high prevalence of atrial fibrillation. Exome sequencing of 5 affected members identified a single novel missense variant in a highly conserved residue of FLNC (filamin C; p.V2297M). FLNC encodes filamin C-a protein that acts as both a scaffold for the assembly and organization of the central contractile unit of striated muscle and also as a mechanosensitive signaling molecule during cell migration and shear stress. Immunohistochemical analysis of FLNC localization in cardiac tissue from an affected family member revealed a diminished localization at the z disk, whereas traditional localization at the intercalated disk was preserved. Stem cell-derived cardiomyocytes mutated to carry the effect allele had diminished contractile activity when compared with controls. We have identified a novel variant in FLNC as pathogenic variant for familial RCM-a finding that further expands on the genetic basis of this rare and morbid cardiomyopathy.
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