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by Stephan Züchner, Peter De Jonghe, Albena Jordanova, et al.Kristl G. Claeys, Velina Guergueltcheva, Sylvia Cherninkova, Steven R. Hamilton, Greg Van Stavern, Karen M. Krajewski, Jeffery Stajich, Ivajlo Tournev, Kristien Verhoeven, Christine T. Langerhorst, Marianne de Visser, Frank Baas, Thomas Bird, Vincent Timmerman, Michael Shy, Jeffery M. Vance
Abstract
Objective Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive. Methods Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. Results In ...
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by Ghizlane Elachouri, Sara Vidoni, Claudia Zanna, et al.Alexandre Pattyn, Hassan Boukhaddaoui, Karen Gaget, Patrick Yu-Wai-Man, Giuseppe Gasparre, Emmanuelle Sarzi, Cécile Delettre, Aurélien Olichon, Dominique Loiseau, Pascal Reynier, Patrick F. Chinnery, Agnès Rotig, Valerio Carelli, Christian P. Hamel, Michela Rugolo, Guy Lenaers
Abstract
An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms ...
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by Gavin Hudson, Patrizia Amati-Bonneau, Emma L. Blakely, et al.Joanna D. Stewart, Langping He, Andrew M. Schaefer, Philip G. Griffiths, Kati Ahlqvist, Anu Suomalainen, Pascal Reynier, Robert McFarland, Douglass M. Turnbull, Patrick F. Chinnery, Robert W. Taylor
Abstract
Mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations in genes encoding one of three well-characterized proteins—polγ, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX). ...
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by Mourad Naimi, Sylvie Bannwarth, Vincent Procaccio, et al.Jean Pouget, Claude Desnuelle, Jean-Francois Pellissier, Agnes Rotig, Arnold Munnich, Patrick Calvas, Christian Richelme, Philippe Jonveaux, Giovanni Castelnovo, Melvin Simon, Michel Clanet, Douglas Wallace, Veronique Paquis-Flucklinger
Abstract
ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA ...
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Abstract
Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration. Substantial progress has been made on the genetic ...
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Abstract
Because mitochondrial genes encode proteins essential for aerobic ATP production, mitochondrial DNA defects can cause an energy crisis. These defects fall into two broad categories: primary mutations in mitochondrial DNA and mutations in nuclear genes, whose protein products are involved in mitochondrial DNA maintenance. Evidence is accumulating that both types of defects can cause mitochondrial DNA loss. Hence, regulatory factors, which determine whether mitochondrial DNA molecules are maintained or lost, potentially play a more important role in these disorders than hitherto ...
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Genetics, Vol. 152, No. 1. (May 1999), pp. 179-190
Abstract
Replicative capacity, which is the number of times an individual cell divides, is the measure of longevity in the yeast Saccharomyces cerevisiae. In this study, a process that involves signaling from the mitochondrion to the nucleus, called retrograde regulation, is shown to determine yeast longevity, and its induction resulted in postponed senescence. Activation of retrograde regulation, by genetic and environmental means, correlated with increased replicative capacity in four different S. cerevisiae strains. Deletion of a gene required for the retrograde response, ...
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Abstract
Recent studies have demonstrated that transgenic mice with an increased rate of somatic point mutations in mitochondrial DNA (mtDNA mutator mice) display a premature aging phenotype reminiscent of human aging. These results are widely interpreted as implying that mtDNA mutations may be a central mechanism in mammalian aging. However, the levels of mutations in the mutator mice typically are more than an order of magnitude higher than typical levels in aged humans. Furthermore, most of the aging-like features are not specific ...
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Abstract
Alterations of mitochondrial functions are linked to multiple degenerative or acute diseases. As mitochondria age in our cells, they become progressively inefficient and potentially toxic, and acute damage can trigger the permeabilization of mitochondrial membranes to initiate apoptosis or necrosis. Moreover, mitochondria have an important role in pro-inflammatory signaling. Autophagic turnover of cellular constituents, be it general or specific for mitochondria (mitophagy), eliminates dysfunctional or damaged mitochondria, thus counteracting degeneration, dampening inflammation, and preventing unwarranted cell loss. Decreased expression of genes ...
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Abstract
To explore the role of mitochondrial activity in the aging process, we have lowered the activity of the electron transport chain and adenosine 5′-triphosphate (ATP) synthase with RNA interference (RNAi) in Caenorhabditis elegans. These perturbations reduced body size and behavioral rates and extended adult life-span. Restoring messenger RNA to near-normal levels during adulthood did not elevate ATP levels and did not correct any of these phenotypes. Conversely, inhibiting respiratory-chain components during adulthood only did not reset behavioral rates and did not ...
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Abstract
We have successfully produced ‘Mito-mice’ harbouring a pathogenic mtDNA mutation. We generated the mice by introducing mitochondria with a 4696 base-pair mtDNA deletion (Δ mtDNA4696) into mouse embryos. This deletion encompasses nucleotides 7759–12 454 and includes six tRNA genes and seven structural genes. In Mito-mice, the Δ mtDNA4696 is transmitted maternally, and induces mitochondrial dysfunction in various tissues. Most of the Mito-mice with high proportions of the Δ mtDNA4696 died at about age 6 months due to renal failure. Mito-mice are ...
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Abstract
Age-dependent accumulation of partially deleted mitochondrial DNA (DeltamtDNA) has been suggested to contribute to aging and the development of age-associated diseases including Parkinson's disease. However, the molecular mechanisms underlying the generation and accumulation of DeltamtDNA have not been addressed in vivo. In this study, we have developed a mouse model expressing an inducible mitochondria-targeted restriction endonuclease (PstI). Using this system, we could trigger mtDNA double-strand breaks (DSBs) in adult neurons. We found that this transient event leads to the generation of ...
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Aging, Vol. 3, No. 8. (August 2011), pp. 754-767
Abstract
The age-associated decline in tissue function has been attributed to ROS-mediated oxidative damage due to mitochondrial dysfunction. The long-lived Ames dwarf mouse exhibits resistance to oxidative stress, a physiological characteristic of longevity. It is not known, however, whether there are differences in the electron transport chain (ETC) functions in Ames tissues that are associated with their longevity. In these studies we analyzed enzyme activities of ETC complexes, CI-CV and the coupled CI-CII and CII-CIII activities of mitochondria from several tissues of ...
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Abstract
Low levels of somatic mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these mutations is unknown. In contrast, mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic β-cells may be extremely sensitive to the accumulation of mtDNA mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO2. Type 2 diabetes arises when β-cells fail ...
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by Andreas Bender, Kim J. Krishnan, Christopher M. Morris, et al.Geoffrey A. Taylor, Amy K. Reeve, Robert H. Perry, Evelyn Jaros, Joshua S. Hersheson, Joanne Betts, Thomas Klopstock, Robert W. Taylor, Douglass M. Turnbull
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Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 40. (4 October 2005), pp. 14392-14397, doi:10.1073/pnas.0502896102
Abstract
Frequently, mtDNA with pathogenic mutations coexist with wild-type genomes (mtDNA heteroplasmy). Mitochondrial dysfunction and disease ensue only when the proportion of mutated mtDNAs is high, thus a reduction in this proportion should provide an effective therapy for these disorders. We developed a system to decrease specific mtDNA haplotypes by expressing a mitochondrially targeted restriction endonuclease, ApaLI, in cells of heteroplasmic mice. These mice have two mtDNA haplotypes, of which only one contains an ApaLI site. After transfection of cultured hepatocytes with ...
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Abstract
When mitochondrial respiration or ubiquinone production is inhibited in Caenorhabditis elegans, behavioral rates are slowed and lifespan is extended. Here, we show that these perturbations increase the expression of cell-protective and metabolic genes and the abundance of mitochondrial DNA. This response is similar to the response triggered by inhibiting respiration in yeast and mammalian cells, termed the "retrograde response". As in yeast, genes switched on in C. elegans mitochondrial mutants extend lifespan, suggesting an underlying evolutionary conservation of mechanism. Inhibition of ...
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Abstract
Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a Surf1−/− recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of −/−, +/+ and +/− genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of Surf1 is compatible with postnatal survival. The biochemical and assembly COX defect was ...
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Abstract
To investigate mtDNA recombination induced by multiple double strand breaks (DSBs) we used a mitochondria-targeted form of the ScaI restriction endonuclease to introduce DSBs in heteroplasmic mice and cells in which we were able to utilize haplotype differences to trace the origin of recombined molecules. ScaI cleaves multiple sites in each haplotype of the heteroplasmic mice (five in NZB and three in BALB mtDNA) and prolonged expression causes severe mtDNA depletion. After a short pulse of restriction enzyme expression followed by ...
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Abstract
The ability to manipulate mitochondrial DNA (mtDNA) heteroplasmy would provide a powerful tool to treat mitochondrial diseases. Recent studies showed that mitochondria-targeted restriction endonucleases can modify mtDNA heteroplasmy in a predictable and efficient manner if it recognizes a single site in the mutant mtDNA. However, the applicability of such model is limited to mutations that create a novel cleavage site, not present in the wild-type mtDNA. We attempted to extend this approach to a 'differential multiple cleavage site' model, where an ...
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Journal of radiation research, Vol. 45, No. 3. (September 2004), pp. 415-422
Abstract
The aim of the study was to investigate the spectrum and frequencies of chromosome aberrations induced by the exposure of different mouse spermatogenic germ cell stages to ionizing radiation. Male mice were exposed in vivo to X-rays. Chromosome aberrations were analyzed in first- and second-embryonic cleavages obtained from mating irradiated males with nonirradiated females at different periods after radiation exposure. A combination of telomeric and centromeric labeling as well as whole Y chromosome painting was used to characterize the rejoining pattern ...
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Genes & development, Vol. 9, No. 5. (1 March 1995), pp. 509-520
Abstract
Poly(ADP-ribosyl)ation is catalyzed by NAD+: protein(ADP-ribosyl) transferase (ADPRT), a chromatin-associated enzyme which, in the presence of DNA breaks, transfers ADP-ribose from NAD+ to nuclear proteins. This post-translational modification has been implicated in many fundamental processes, like DNA repair, chromatin stability, cell proliferation, and cell death. To elucidate the biological function of ADPRT and poly(ADP-ribosyl)ation in vivo the gene was inactivated in the mouse germ line. Mice homozygous for the ADPRT mutation are healthy and fertile. Analysis of mutant tissues and fibroblasts ...
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Proc Natl Acad Sci U S A, Vol. 94, No. 14. (8 July 1997), pp. 7303-7307
by J. M. de Murcia, C. Niedergang, C. Trucco, et al.M. Ricoul, B. Dutrillaux, M. Mark, F. J. Oliver, M. Masson, A. Dierich, M. LeMeur, C. Walztinger, P. Chambon, G. de Murcia
Abstract
Poly(ADP-ribose) polymerase [PARP; NAD+ ADP-ribosyltransferase; NAD+: poly(adenosine-diphosphate-D-ribosyl)-acceptor ADP-D-ribosyltransferase, EC 2.4.2.30] is a zinc-finger DNA-binding protein that detects specifically DNA strand breaks generated by genotoxic agents. To determine its biological function, we have inactivated both alleles by gene targeting in mice. Treatment of PARP-/- mice either by the alkylating agent N-methyl-N-nitrosourea (MNU) or by gamma-irradiation revealed an extreme sensitivity and a high genomic instability to both agents. Following whole body gamma-irradiation (8 Gy) mutant mice died rapidly from acute radiation toxicity to ...
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Abstract
Spermatogonial stem cells (SSCs) are the foundation for spermatogenesis and, thus, preservation of a species. Because of stem cell rarity, studying their self-renewal is greatly facilitated by in vitro culture of enriched biologically active cell populations. A recently developed culture method identified glial cell line-derived neurotrophic factor (GDNF) as the essential growth factor that supports in vitro self-renewal of SSCs and results in an increase in their number. This system is a good model to study mechanisms of stem cell self-renewal ...
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Abstract
As genetic information is transmitted through successive generations, it passes between pluripotent cells in the early embryo and germ cells in the developing foetus and adult animal. Tex19.1 encodes a protein of unknown function, whose expression is restricted to germ cells and pluripotent cells. During male spermatogenesis, Tex19.1 expression is highest in mitotic spermatogonia and diminishes as these cells differentiate and progress through meiosis. In pluripotent stem cells, Tex19.1 expression is also downregulated upon differentiation. However, it is not clear whether ...
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Abstract
Gene-targeted knockout mice have been generated lacking the major uracil-DNA glycosylase, UNG. In contrast to ung − mutants of bacteria and yeast, such mice do not exhibit a greatly increased spontaneous mutation frequency. However, there is only slow removal of uracil from misincorporated dUMP in isolated ung −/− nuclei and an elevated steady-state level of uracil in DNA in dividing ung −/− cells. A backup uracil-excising activity in tissue extracts from ung null mice, with properties indistinguishable from the mammalian SMUG1 ...
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Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 23. (9 November 1999), pp. 13300-13305
Abstract
DNA damage generated by oxidant byproducts of cellular metabolism has been proposed as a key factor in cancer and aging. Oxygen free radicals cause predominantly base damage in DNA, and the most frequent mutagenic base lesion is 7,8-dihydro-8-oxoguanine (8-oxoG). This altered base can pair with A as well as C residues, leading to a greatly increased frequency of spontaneous G.C-->T.A transversion mutations in repair-deficient bacterial and yeast cells. Eukaryotic cells use a specific DNA glycosylase, the product of the OGG1 gene, ...
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Nucleic acids research, Vol. 29, No. 8. (15 April 2001), pp. 1781-1790
Abstract
The quality of germ cell DNA is critical for the fate of the offspring, yet there is limited knowledge of the DNA repair capabilities of such cells. One of the main DNA repair pathways is base excision repair (BER) which is initiated by DNA glycosylases that excise damaged bases, followed by incision of the generated abasic (AP) sites. We have studied human and rat methylpurine-DNA glycosylase (MPG), uracil-DNA glycosylase (UNG), and the major AP endonuclease (HAP1/APEX) in male germ cells. Enzymatic ...
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Nucleic acids research, Vol. 29, No. 8. (15 April 2001), pp. 1791-1800
Abstract
The acquisition of genotoxin-induced mutations in the mammalian germline is detrimental to the stable transfer of genomic information. In somatic cells, nucleotide excision repair (NER) is a major pathway to counteract the mutagenic effects of DNA damage. Two NER subpathways have been identified, global genome repair (GGR) and transcription-coupled repair (TCR). In contrast to somatic cells, little is known regarding the expression of these pathways in germ cells. To address this basic question, we have studied NER in rat spermatogenic cells ...
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Abstract
Male reproductive health has received considerable attention in recent years. In addition to declining sperm quality, fertility problems and increased incidence of testicular cancer, there is accumulating evidence that genetic damage, in the form of unrepaired DNA lesions or de novo mutations, may be transmitted via sperm to the offspring. Such genetic damage may arise from environmental exposure or via endogenously formed reactive species, in stem cells or during spermatogenesis. Damaged testicular cells not removed by apoptosis rely on DNA repair ...
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Abstract
In a recent Viewpoint on missing heritability (Missing heritability and strategies for finding the underlying causes of complex disease. Nature Rev. ...
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Abstract
Programmed cell death (PCD) plays a key role in developmental biology and in maintenance of the steady state in continuously renewing tissues. Currently, its existence is inferred mainly from gel electrophoresis of a pooled DNA extract as PCD was shown to be associated with DNA fragmentation. Based on this observation, we describe here the development of a method for the in situ visualization of PCD at the single-cell level, while preserving tissue architecture. Conventional histological sections, pretreated with protease, were nick ...
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Analytical biochemistry, Vol. 72 (7 May 1976), pp. 248-254
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Abstract
A procedure is described which permits the isolation from the prepuberal mouse testis of highly purified populations of primitive type A spermatogonia, type A spermatogonia, type B spermatogonia, preleptotene primary spermatocytes, leptotene and zygotene primary spermatocytes, pachytene primary spermatocytes and Sertoli cells. The successful isolation of these prepuberal cell types was accomplished by: (a) defining distinctive morphological characteristics of the cells, (b) determining the temporal appearance of spermatogenic cells during prepuberal development, (c) isolating purified seminiferous cords, after dissociation of the ...
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Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 22. (23 October 2001), pp. 12566-12571, doi:10.1073/pnas.221232998
Abstract
O(6)-methylguanine (O(6)mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O(6)mG through a direct reversal mechanism by a protein termed O(6)-methylguanine-DNA methyltransferase (MGMT). However, the contribution of O(6)mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB/FeJ mice expressing human MGMT (hMGMT) were generated ...
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posted to mouse_models spermatozoa
by ksvogel
on 2010-07-12 20:16:33
Abstract
BACKGROUND: Spermatozoal DNA damage is associated with poor sperm quality, disturbed embryonic development and early embryonic loss, and some genetic diseases originate from paternal de novo mutations. We previously reported poor repair of bulky DNA-lesions in rodent testicular cells. METHODOLOGY/PRINCIPAL FINDINGS: We studied the fate of DNA lesions in the male germ line. B[a]PDE-N(2)-dG adducts were determined by liquid chromatography-tandem mass spectrometry, and de novo mutations were measured in the cII-transgene, in Big Blue mice exposed to benzo[a]pyrene (B[a]P; 3 x ...
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Abstract
10.1073/pnas.0602432103 ...
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Abstract
The high steady-state level of mitochondrial DNA (mtDNA) oxidative lesions is assumed to be the result of high susceptibility to DNA damage attack and limited DNA repair capacity in mitochondria. As a key enzyme of base excision repair (BER), human apurinic/apyrimidinic endonuclease (APE1) is often scarce in mitochondria, and mitochondria-targeted APE1 with robust repair activity represents a promising therapeutic candidate. In this study, overexpression vectors of mitochondria-targeted truncated APE1 (mtAPE1) and that of full-length APE1 (flAPE1) were constructed and transfected to ...
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Abstract
Objective Our goal was to test the hypothesis that spermatozoal chromatin packaging changes with age and that aging affects the susceptibility of spermatozoal DNA to oxidative damage. Design Laboratory study. Setting Academic facility. Patient(s) Young (4 months) and old (21 months) Brown Norway rats. Intervention(s) Spermatozoa were collected from the cauda epididymidis and were incubated in saline or H 2 O 2 . Main Outcome Measurement(s) Thiols levels, chromatin condensation, DNA susceptibility to acid-induced DNA denaturation, and DNA damage were ...
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Abstract
BACKGROUND: The goals of our study were to examine chromatin packaging and integrity in spermatozoa taken from the caput and cauda epididymides of young (4-month-old) and old (21-month-old) Brown Norway rats and to assess whether spermatozoal sensitivity to oxidative treatments is altered with age. METHODS: Oxidative treatments consisted of (i) in vivo oxidative challenge by systemic administration of the glutathione-depleting drug L-buthionine-[S,R]-sulphoximine (BSO) and (ii) in vitro oxidative challenge by incubating collected spermatozoa with hydrogen peroxide (H2O2). Chromatin parameters assessed included ...
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Abstract
In many organisms, programmed cell death of germ cells is required for normal development. This often occurs through highly conserved events including the transfer of vital cellular material to the growing gametes following death of neighboring cells. Germline cell death also plays a role in such diverse processes as removal of abnormal or superfluous cells at certain checkpoints, establishment of caste differentiation, and individualization of gametes. This review focuses on the cell death events that occur during gametogenesis in both vertebrates ...
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Abstract
This study was designed to explore the relationship between men's age and DNA damage and apoptosis in human spermatozoa. Semen samples were collected from men between the ages of 20 and 57 years. Sperm DNA double-strand breaks were assessed using the neutral microgel electrophoresis (comet) assay, and apoptosis was estimated using the DNA diffusion assay. Academic medical center. Sixty-six men aged 20 to 57 years were recruited from infertility laboratory and general populations and consented to donate a semen sample. Recruitment ...
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Abstract
AP endonuclease (APE), with dual activities as an endonuclease and a 3′ exonuclease, is a central player in repair of oxidized and alkylated bases in the genome via the base excision repair (BER) pathway. APE acts as an endonuclease in repairing AP sites generated spontaneously or after base excision during BER. It also removes the 3′ blocking groups in DNA generated directly by ROS or after AP lyase reaction. In contrast to E. coli and lower eukaryotes which express two distinct ...
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Nucleic acids research, Vol. 22, No. 23. (25 November 1994), pp. 4884-4889
Abstract
The HAP1 protein (also known as APE/Ref-1) is a bifunctional human nuclear enzyme required for repair of apurinic/apyrimidinic sites in DNA and reactivation of oxidized proto-oncogene products. To gain insight into the biological roles of HAP1, the effect of expressing antisense HAP1 RNA in HeLa cells was determined. The constructs for antisense RNA expression consisted of either a full-length HAP1 cDNA or a genomic DNA fragment cloned downstream of the CMV promoter in pcDNAneo. Stable HeLa cell transfectants expressing HAP1 antisense ...
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Abstract
Apert syndrome results from one or other of two specific nucleotide substitutions, both CG transversions, in the fibroblast growth factor receptor 2 (FGFR2) gene. The frequency of new mutations, estimated as 1 per 65,000 live births, implies germline transversion rates at these two positions are currently the highest known in the human genome. Using a novel application of the amplification refractory mutation system (ARMS), we have determined the parental origin of the new mutation in 57 Apert families: in every case, ...
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Abstract
Achondroplasia (ACH) is the most common genetic form of dwarfism. This disorder is inherited as an autosomal dominant trait, although the majority of cases are sporadic. A gene for ACH was recently localized to 4p 16.3 by linkage analyses. The ACH candidate region includes the gene encoding fibroblast growth factor receptor 3 (FGFR3), which was originally considered as a candidate for the Huntington's disease gene. DNA studies revealed point mutations in the FGFR3 gene in ACH heterozygotes and homozygotes. The mutation ...
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American journal of human genetics, Vol. 41, No. 2. (August 1987), pp. 218-248
Abstract
A statistical analysis of parental age and the incidence of new mutation has been performed. Some new data on Apert, Crouzon, and Pfeiffer syndromes is presented and combined with all available data from the literature on parental age and new mutation. Significant heterogeneity among syndromes for the rate of increase in incidence with parental age was found. A parsimonious conclusion is that mutations fall into two groups, one with a high rate of increase with age and the other with a ...
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