Changes in Channel Trafficking and Protein Stability Caused by LQT2 Mutations in the PAS Domain of the HERG Channel

Inherited human long-QT2 syndrome (LQTS) results from mutations in the gene encoding the HERG channel. Several LQT2-associated mutations have been mapped to the amino terminal cytoplasmic Per-Arnt-Sim (PAS) domain of the HERG1a channel subunit. Here we have characterized the trafficking properties of some LQT2-associated PAS domain mutants and analyzed rescue of the trafficking mutants by low temperature (27°C) or by the pore blocker drug E4031. We show that the LQT2-associated mutations in the PAS domain of the HERG channel display molecular properties that are distinct from the properties of LQT2-associated mutations in the trans-membrane region. Unlike the latter, many of the tested PAS domain LQT2-associated mutations do not result in trafficking deficiency of the channel. Moreover, the majority of the PAS domain mutations that cause trafficking deficiencies are not rescued by a pore blocking drug. We have also explored the in vitro folding stability properties of isolated mutant PAS domain proteins using a thermal unfolding fluorescence assay and a chemical unfolding assay

Clinical diagnosis of Long QT Syndrome: back to the caliper.

In the last 10 years, the management of cardiac arrhythmias has evolved to an impressive pace, thanks to the development of highly sophisticated technologies for diagnosis and treatment. Mapping of the site of origin of arrhythmias, ablation, and implant of defibrillators have reduced the importance of the traditional approaches based on electrocardiographic reading and prescription of drugs. In this context, inherited arrhythmogenic diseases such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and Brugada syndrome represent the exception in which the ECG has remained the pivotal diagnostic tool. When approaching the diagnosis of one of these diseases, the cardiologist has to leave fancy computer screens and go back to the ‘ruler and caliper’ to measure the duration of an ‘interval’ or the elevation of an electrocardiographic ‘segment’. This apparently simple diagnosis, however, is far from being easy and even ‘experts’ in the field may face substantial diagnostic dilemma

New insights into the long-QT syndrome

The long QT syndrome (LQTS) is an arrhythmogenic disease in which the prolongation of cardiac repolarization alters the heart's electrical stability and predisposes affected individuals to cardiac arrest. The first arrhythmic events occur during adolescence, and are largely triggered by increased sympathetic activity. Mutations in genes encoding ion channels or proteins that control these channels have emerged as the basis of LQTS. The molecular investigation of LQTS flourished from the mid-nineties. At present, 70% of the population can be genotyped LQTS. Researchers are looking for other causative genes, and have even ventured into non-coding regions of LQTS genes in an attempt to genotype the remaining 30% of patients with LQTS. It has also developed strategies to integrate genotyping in clinical practice. In the clinical setting, the tremendous effort invested in major international registrations of LQTS is already bearing fruit. These studies provide new data on the natural history of LQTS and the response to treatment of patients with genotyped LQTS. This editorial and the accompanying review article published in this edition of Spanish Journal of Cardiology highlights recent advances relevant to the clinical management of affected patients

The Brugada syndrome

PURPOSE OF REVIEW: The Brugada syndrome has been an area of intensive investigation since its earliest description in 1992, both on a clinical and on a basic research level. In this review, we will focus on recent achievements in the molecular dissection of the disease pathophysiology and on large multicenter studies dealing with prognostic markers and the natural history of the Brugada syndrome. RECENT FINDINGS: In the past year, two additional genetic pathways have been associated with the disease. Also, an inflammatory or infectious etiology has recently been linked with the Brugada syndrome. The debate on the predictive role of programmed electrical stimulation is still ongoing. Very recently, large follow-up studies questioned the prognostic role of programmed electrical stimulation in this disease. SUMMARY: Knowledge on the genetic determinants of the Brugada syndrome remains limited. Therefore, the management and the risk stratification of patients should be performed on a clinical basis. Sufficient evidence exists to reassure clinicians who feel reluctant to include programmed electrical stimulation in the risk stratification strategy of asymptomatic Brugada syndrome patients

Unconventional intronic splice site mutation in SCN5A associates with cardiac sodium channelopathy

Background: Mutations in the cardiac sodium channel, SCN5A, have been associated with one type of long-QT syndrome, with isolated cardiac conduction defects and Brugada syndrome. The sodium channelopathies exhibit marked variation in clinical phenotypes. The mechanisms underlying the phenotypical diversity, however, remain unknown. Exonic SCN5A mutations can be detected in 20% of Brugada syndrome patients. Results: An intronic mutation (c.4810+3_4810+6dupGGGT) in the SCN5A gene, located outside the consensus splice site, was detected in this study in a family with a highly variable clinical phenotype of Brugada syndrome and/or conduction disease and in a patient with Brugada syndrome. The mutation was not found in a control panel of 100 (200 alleles) ethnically matched normal control subjects. We provide in vivo and in vitro evidence that the mutation can disrupt the splice donor site, activate a cryptic splice site, and create a novel splice site. Notably, our data show that normal transcripts can be also derived from the mutant allele. Conclusions: This is the first report of an unconventional intronic splice site mutation in the SCN5A gene leading to cardiac sodium channelopathy. We speculate that its phenotypical diversity might be determined by the ratio of normal/abnormal transcripts derived from the mutant allele

Three-dimensional rotational angiography during left or right atrial ablation procedures: acquisition during adenosine-induced ventricular asystole vs. rapid ventricular pacing

Ector J., De Buck S., Nuyens D., Rossenbacker T., Gopal R., Willems R., Maes F., Heidbüchel H., ''Three-dimensional rotational agiography during left or right atrial ablation procedures : acquisition during adenosine-induced ventricular asystole vs. rapid ventricular pacing'', Acta Cardiologica, vol. 63, no. 5, pp. 654 (2nd Belgian heart rhythm meeting ‘Arrhythmias for every cardiologist’, October 2-4, 2008, Brussels, Belgium).status: publishe

Role of RENAL nephrometry scoring system in planning surgical intervention in patients with localized renal mas

Purpose: The study was designed to validate the value of preoperative planning using RENAL nephrometry scoring system in patients having organ confined renal tumors and undergoing surgical intervention and to assess its correlation with the surgical technique. Patient and methods: Forty patients with organ-confined renal masses underwent RENAL nephrometry scoring which was correlated with the surgical technique either radical or nephron-sparing surgery. Result: RENAL nephrometry scoring system shows correlation with the type of surgery of resection of the renal tumors. Conclusion: RENAL nephrometry score system is an objective method to help in the decision of surgical approach to resect organ confined renal tumors