A novel LMNA mutation (R189W) in familial dilated cardiomyopathy: evidence for a 'hot spot' region at exon 3: a case report

We describe a case of a patient with idiopathic dilated cardiomyopathy and cardiac conduction abnormalities who presented a strong family history of sudden cardiac death. Genetic screening of lamin A/C gene revealed in proband the presence of a novel missense mutation (R189W), near the most prevalent lamin A/C mutation (R190W), suggesting a "hot spot" region at exon 3

The Radiation Issue in Cardiology: the time for action is now

The "radiation issue" is the need to consider possible deterministic effects (e.g., skin injuries) and long-term cancer risks due to ionizing radiation in the risk-benefit assessment of diagnostic or therapeutic testing. Although there are currently no data showing that high-dose medical studies have actually increased the incidence of cancer, the "linear-no threshold" model in radioprotection assumes that no safe dose exists; all doses add up in determining cancer risks; and the risk increases linearly with increasing radiation dose. The possibility of deterministic effects should also be considered when skin or lens doses may be over the threshold. Cardiologists have a special mission to avoid unjustified or non-optimized use of radiation, since they are responsible for 45% of the entire cumulative effective dose of 3.0 mSv (similar to the radiological risk of 150 chest x-rays) per head per year to the US population from all medical sources except radiotherapy. In addition, interventional cardiologists have an exposure per head per year two to three times higher than that of radiologists. The most active and experienced interventional cardiologists in high volume cath labs have an annual exposure equivalent to around 5 mSv per head and a professional lifetime attributable to excess cancer risk on the order of magnitude of 1 in 100. Cardiologists are the contemporary radiologists but sometimes imperfectly aware of the radiological dose of the examination they prescribe or practice, which can range from the equivalent of 1-60 mSv around a reference dose average of 10-15 mSv for a percutaneous coronary intervention, a cardiac radiofrequency ablation, a multi-detector coronary angiography, or a myocardial perfusion imaging scintigraphy. A good cardiologist cannot be afraid of life-saving radiation, but must be afraid of radiation unawareness and negligence

Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

<p>Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.</p> <p>Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.</p> <p>Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.</p> <p>Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.</p&gt

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population

Ectodermal-Neural Cortex 1 Down-Regulates Nrf2 at the Translational Level

The transcription factor Nrf2 is the master regulator of a cellular defense mechanism against environmental insults. The Nrf2-mediated antioxidant response is accomplished by the transcription of a battery of genes that encode phase II detoxifying enzymes, xenobiotic transporters, and antioxidants. Coordinated expression of these genes is critical in protecting cells from toxic and carcinogenic insults and in maintaining cellular redox homeostasis. Activation of the Nrf2 pathway is primarily controlled by Kelch-like ECH-associated protein 1 (Keap1), which is a molecular switch that turns on or off the Nrf2 signaling pathway according to intracellular redox conditions. Here we report our finding of a novel Nrf2 suppressor ectodermal-neural cortex 1 (ENC1), which is a BTB-Kelch protein and belongs to the same family as Keap1. Transient expression of ENC1 reduced steady-state levels of Nrf2 and its downstream gene expression. Although ENC1 interacted with Keap1 indirectly, the ENC1-mediated down-regulation of Nrf2 was independent of Keap1. The negative effect of ENC1 on Nrf2 was not due to a change in the stability of Nrf2 because neither proteasomal nor lysosomal inhibitors had any effects. Overexpression of ENC1 did not result in a change in the level of Nrf2 mRNA, rather, it caused a decrease in the rate of Nrf2 protein synthesis. These results demonstrate that ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation, which adds another level of complexity in controlling the Nrf2 signaling pathway

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil

<p>Abstract</p> <p>Background/Aim</p> <p>Hyperhomocysteinemia due to Methylenetetrahydrofolate Reductase (<it>MTHFR</it>) gene, in particular the C677T (Ala222Val) polymorphism were recently associated to steatosis and fibrosis. We analyzed the frequency of <it>MTHFR </it>gene in a cross-sectional study of patients affected by Chronic Hepatitis C (CHC) from Northeast of Brazil.</p> <p>Method</p> <p>One hundred seven-four untreated patients with CHC were genotyped for the C677T <it>MTHFR</it>. Genomic DNA was extracted from peripheral blood cells and the C677T <it>MTHFR </it>polymorphism was identified by PCR-RFLP. The homocysteine (Hcy) levels were determined by chemiluminescence method. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and have current and past daily alcohol intake less than 100 g/week.</p> <p>Results</p> <p>Among subjects infected with CHC genotype non-1 the frequency of <it>MTHFR </it>genotypes TT was 9.8% <it>versus </it>4.4% genotype 1 (p = 0.01). Nevertheless, association was found between the <it>MTHFR </it>genotype TT × CT/CC polymorphism and the degree of steatosis and fibrosis in both hepatitis C genotype (p < 0.05). A significant difference was found on plasma Hcy levels in patients with steatosis regardless of HCV genotype (p = 0.03).</p> <p>Conclusion</p> <p>Our results indicate that plasma Hcy levels is highly prevalent in subjects with chronic hepatits C with steatosis regardless of HCV genotype and vitamin deficiency. The presence of genotype TT of <it>MTHFR </it>C677T polymorphism was more common in CHC genotype non-1 infected patient regardless of histopathological classification and genotype TT+CT frequencies were significant in the presence of fibrosis grade 1+2 and of steatosis in CHC infected patients from the northeast of Brazil regardless of HCV genotype. The genetic susceptibility of <it>MTHFR </it>C677T polymorphism should be confirmed in a large population.</p

AMPD1 gene mutations are associated with obesity and diabetes in Polish patients with cardiovascular diseases

Previous studies showed an association of the common functional polymorphism (C34T, Gln12Stop) in the adenosine monophosphate deaminase-1 (AMPD1) gene with survival in heart failure (HF) and/or coronary artery disease (CAD). The aim of the study was to search for other mutations in selected regions of the AMPD1 gene in Polish CAD and HF patients, and to analyze their associations with obesity and diabetes. Exons 2, 3, 5, and 7 of AMPD1 were scanned for mutations in 97 patients with CAD without HF (CAD+ HF−), 104 patients with HF (HF+), and 200 newborns from North-Western Poland using denaturing high-performance liquid chromatography (DHPLC), polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and direct sequencing. Frequencies of AMPD1 C34T mutation, as well as novel A99G, G512A, IVS4-6delT, and C784T sequence alterations, were similar in the three groups, but 860T mutated allele was less frequent in the combined CAD+ HF− and HF+ groups than in the controls (1.7% vs. 4.3%, p = 0.040). Heterozygous 34CT genotype was associated with lower (odds ratio [OR] = 0.32, 95% confidence interval [CI] = 0.13–0.81) and 860AT with higher (OR = 13.7, 95%CI = 1.6–118) prevalence of diabetes or hyperglycemia in relation to wild-type homozygotes. Abdominal obesity was more frequent in 860AT patients than in wild-type homozygotes and 34CT heterozygotes (86% vs. 40% vs. 29%, p < 0.05). Nine genes containing polymorphisms linked with AMPD1 C34T mutation were found in the HapMap database. AMPD1 C34T nonsense mutation is associated with reduced prevalence of diabetes and obesity in patients with CAD or HF, but A860T substitution seems to exert opposite metabolic effects and should always be accounted for in the studies of the AMPD1 genotype

Alternative splicing of exon 10 in the tau gene as a target for treatment of tauopathies

Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies