Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.
Proteins identified in this work might be useful markers to eventually distinguish CsA toxicity from chronic allograft nephropathy in protocol biopsies of transplanted patients, facilitating the adjustment of CsA doses to non-toxic ranges, as well as to study the impact of potential therapeutic interventions in an animal model.
The present study aimed to develop a set of sensitive assays to evaluate the presence of different isoforms, the activity degree, and the immunolocalisation of proacrosin-acrosin in sexually mature boars. The goal was to determine the proacrosin-acrosin status of boar spermatozoa throughout epididymal maturation, during ejaculation and after in vitro capacitation. In epididymal samples, proacrosin expression was high in all regions studied. In contrast, α- and β-acrosin expression was low in the caput region, and increased progressively during maturation and in vitro capacitation. In in vitro capacitated samples, the acrosin activity was 2.25 times higher than in the ejaculated samples and immunolocalisation analyses showed redistribution of proacrosin-acrosin at the apical ridge of the head. This study provides relevant data about the expression, localisation and activity of the proacrosin-acrosin system in healthy adult boars that can be used as a base to analyse changes in the proacrosin-acrosin system under pathological conditions.
Sudden cardiac death is defined as an unexpected decease of cardiac origin. In individuals under 35 years old, most of these deaths are due to familial arrhythmogenic syndromes of genetic origin, also known as channelopathies. These familial cardiac syndromes commonly follow an autosomal dominant pattern of inheritance. Diagnosis, however, can be difficult, mainly due to incomplete penetrance and variable expressivity, which are hallmarks in these syndromes. The clinical manifestation of these diseases can range from asymptomatic to syncope but sudden death can sometimes be the first symptom of disease. Early identification of at-risk individuals is crucial to prevent a lethal episode. In this review, we will focus on the genetic basis of channelopathies and the effect of genetic and non-genetic modifiers on their phenotypes.
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