Inherited neuromuscular disorder (NMD) is a wide term covering different genetic disorders affecting muscles, nerves, and neuromuscular junctions. Genetic and clinical heterogeneity is the main ...drawback in a routine gene‐by‐gene diagnostics. We present Czech NMD patients with a genetic cause identified using targeted next‐generation sequencing (NGS) and the spectrum of these causes. Overall 167 unrelated patients presenting NMD falling into categories of muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, and other myopathies were tested by targeted NGS of 42 known NMD‐related genes. Pathogenic or probably pathogenic sequence changes were identified in 79 patients (47.3%). In total, 37 novel and 51 known disease‐causing variants were detected in 23 genes. In addition, variants of uncertain significance were suspected in 7 cases (4.2%), and in 81 cases (48.5%) sequence changes associated with NMD were not found. Our results strongly indicate that for molecular diagnostics of heterogeneous disorders such as NMDs, targeted panel testing has a high‐clinical yield and should therefore be the preferred first‐tier approach. Further, we show that in the genetic diagnostic practice of NMDs, it is necessary to take into account different types of inheritance including the occurrence of an autosomal recessive disorder in two generations of one family.
The X-linked CDKL5 gene, which encodes cyclin-dependent kinase-like 5 protein, has been implicated in early-onset encephalopathy and atypical Rett syndrome with early-onset seizures. The CDKL5 ...protein is a kinase required for neuronal development and morphogenesis, but its precise functions are still largely unexplored. Individuals with CDKL5 mutations present with severe global developmental delay, intractable epilepsy, and Rett-like features. A clear genotype-phenotype correlation has not been established due to an insufficient number of reported cases. The aim of this study was to analyse the CDKL5 gene in Czech patients with early-onset seizures and Rett-like features. We performed mutation screening in a cohort of 83 individuals using high-resolution melting analysis, DNA sequencing and multiplex ligation- dependent probe amplification. Molecular analyses revealed heterozygous pathogenic mutations in three girls with severe intellectual disability and intractable epilepsy starting at the age of two months. All three identified mutations, c.637G>A, c.902_977+29del105, and c.1757_1758delCT, are novel, thus significantly extending the growing spectrum of known pathogenic CDKL5 sequence variants. Our results support the importance of genetic testing of the CDKL5 gene in patients with early-onset epileptic encephalopathy and Rett-like features with early-onset seizures. This is the first study referring to molecular defects of CDKL5 in Czech cases.
There is an increasing evidence that dietary phytochemicals may play important roles as chemopreventive or chemotherapeutic agents in prevention of many diseases, including tumors. The purpose of ...this study was to examine antimutagenic effects and effect on the immune response of representative series of substances which commonly occur in human diet. Using the Ames bacterial mutagenicity test and in vivo chemiluminescence test, we investigated antigenotoxic and immunomodulatory effects of juices and vegetable homogenates (carrot + cauliflower, cauliflower, red cabbage, broccoli, onion, garlic) on the genotoxicity of AFB1 and pyrolysates of aminoacids. Using the Ames test and in vivo micronucleus, the chemiluminescence test, the blastic transformation test and the comet assay we examined antimutagenic effects of chemically identified chemoprotective substances in the pure form (resveratrol, diallylsulphide, phenethyl isothiocyanate, ellagic acid, epigallocatechin gallate, genistein and curcumin) on mutagenicity induced by three reference mutagens: aflatoxin B1 (AFB1), 2-amino-3-metylimidazo4,5,-f chinolin (IQ) and N-nitroso- N-metylurea (MNU) and effect of phytochemicals on the immunosuppression caused by these mutagens. All complete vegetable homogenates and substances of plant origin tested, showed a clear antimutagenic and immunomodulatory activities on mutagenicity and immunosuppression induced by reference mutagens. Only in the Ames test the effect of some phytochemicals against direct mutagen MNU was lower compared to indirect mutagens AFB1 and IQ. Similarly, resveratrol and epigallocatechin gallate had no inhibitory effect on mutagenicity MNU in the Ames test.
Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, ...including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment.
The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Most radiosensitivity syndromes are autosomal recessively inherited; examples are ataxia teleangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome and Werner syndrome.
Radiotherapy is contraindicated in most homozygous patients with recessive radiosensitivity syndromes. Asymptomatic heterozygotes may have an increased risk of tumor incidence and a small part of them slightly increased risk of RT intolerance; however, this does not limit RT treatment. The high risk of secondary malignancies after radiotherapy is a contraindication to adjuvant RT in Li-Fraumeni syndrome.
A wide array of antioxidative and anti-inflammatory substances derived from edible plants have been reported to possess chemopreventive and chemoprotective activities. Among the most extensively ...investigated and well-defined dietary chemopreventives is curcumin. Using the Ames test and in vivo micronucleus test, chemiluminescence test, blastic transformation test, and comet assay, we examined the antimutagenic effects of the chemically identified chemoprotective substance curcumin (diferuloylmethane) in the pure form on mutagenicity induced by three reference mutagens: aflatoxin B1 (AFB1), 2-amino-3-metylimidazo4,5-fquinoline (IQ), and N-nitroso-N-metylurea (MNU), and the effect of curcumin on the immunosuppression caused by these mutagens. Curcumin in the pure form showed a clear antimutagenic and immunomodulatory activities on mutagenicity and immunosuppression induced by reference mutagens.
Using the Ames bacterial mutagenicity test and an in vivo micronucleus test, we investigated the antigenotoxic effect of ellagic acid on the genotoxicity of three mutagens: ...amino-methylimidazo-quinoline (IQ), aflatoxin B1 (AFB1), and N-nitroso-N-methylurea (MNU). The concentration of 300 microg/plate had the strongest effect on mutagenicity of all concentrations of IQ in strain TA98 of Salmonella typhimurium, whereas in strain TA100, the concentration of 30 microg per dish of ellagic acid was more effective than 300 microg per plate. Thirty microg/plate of ellagic acid had a much greater antimutagenic effect on both strains tested than 300 microg/plate when different concentrations of AFB1 were used. The mutagenic effect of MNU was only weakly reduced by the ellagic acid used in high concentrations. In the micronucleus test, three-day oral application of ellagic acid prior to the applicaton of AFB1, IQ, or MNU, respectively, markedly reduced the numbers of micronuclei induced by these three mutagens in polychromatophilic erythrocytes of mice. Ellagic acid prevented the negative effects of mutagens in one of the phases of phagocytosis as measured by chemiluminescence.
We investigated the antigenotoxic effect of genistein on the genotoxicity of three mutagens and carcinogens as follows: aflatoxine B1 (AFB1), 2-amino-3-methylimidazo 4,5-fquinoline (IQ), and ...N-nitroso-N-methylurea (MNU), using the Ames bacterial mutagenicity test and the micronucleus test. In the Ames test on Salmonella typhimurium, a significant antimutagenic effect was determined against the indirect mutagen AFB1 in two strains, TA98 and TA100. However, the effect on the IQ indirect mutagenicity was more pronounced in the test with TA98 than with TA100. The mutagenicity of the direct mutagen MNU was suppressed by genistein only at its highest concentration used (300 microg/plate). The protective effect of genistein against all three mutagens was shown in the micronucleus test as the treatment of mice with the combinations of genistein and mutagens resulted in a significant reduction of the number of micronuclei in comparison with the number of micronuclei induced by the individual mutagens alone.
To evaluate the role of angiotensin-converting enzyme (ACE) polymorphism on the development of end-stage dilated cardiomyopathy, the ACE gene polymorphism of 90 patients after heart transplantation ...because of this disease was compared with the population sample. No difference in gene frequencies was found, but when compared with the population sample there were fewer ID heterozygotes detected; no significant influence of ACE polymorphism on the course of the disease before transplantation was found.
Dietary polyamines, putrescine, spermidine and spermine, participate in many biochemical processes, mainly in cell proliferation and differentiation. Polyamines were determined as
N-benzamides by ...micellar electrokinetic capillary chromatography in 153 samples of 21 foods, mostly culinary processed. Very low putrescine contents were observed in processed meats, pork liver and kidney, while the highest mean contents exceeded 55 mg
kg
−1 in stewed green pea, grapefruit and fresh green pepper. Higher spermine than spermidine contents were typical for foods of animal origin, while the opposite was observed in plant products. Mean spermidine contents, exceeding 20 mg
kg
−1, were found in dry soybean, stewed green pea, yellow pea puree and roasted chicken breast. Roasted chicken breast, stewed pork kidney, roasted pork liver and roasted pork neck had mean spermine contents above the same level. Polyamine content varies widely within individual food items, what makes application of the results by dietitians rather difficult.
Antimutagenic effect of resveratrol Langová, Martina; Polívková, Zdeňka; Šmerák, Petr ...
Czech Journal of Food Sciences,
2005, Letnik:
23, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Evidence exists from population-based and laboratory studies that some phytochemicals have protective effects against tumors or other diseases and reveal antimutagenic activity. We studied the ...protective effect of the plant phytoallexin resveratrol on the mutagenic activity of three mutagens, i.e. aflatoxin B1 (AFB1), 2-amino-3-methylimidazo4,5-fqui-noline (IQ) and N-nitroso-N-methylurea (MNU) using the Ames and the micronucleus tests. In the Ames test, we proved a significant antimutagenic activity only against the indirect mutagens AFB1 and IQ, not against the direct mutagen MNU. A significant decrease of mutagenicity of all three mutagens was detected by the micronucleus test.
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