Abstract
Objective Mutations in SCN5A, the gene encoding the α-subunit of the cardiac sodium channel (Nav1.5), have been associated with various inherited arrhythmia syndromes, including Brugada ...syndrome (BrS). Here, we report the functional consequences of a novel missense SCN5A mutation, G1319V, identified in a BrS patient. The G1319V mutation is located in the loop connecting transmembrane segments 4 and 5 in domain III (DIIIS4-S5), a region so far considered to be exclusively involved in fast inactivation.
Methods Whole-cell mutant (G1319V) and wild-type (WT) sodium currents (I
Na) were studied in the Human Embryonic Kidney cell line (HEK-293) transfected with Nav1.5 α-subunit cDNA (WT or mutant) together with hβ1-subunit cDNA, using the patch-clamp technique.
Results Maximal peak I
Na and persistent sodium current were similar in WT and channel G1319V channels. The G1319V mutation shifted the potential of half-maximal (V
1/2) activation towards more positive potentials (+3.7 mV), thereby increasing the degree of depolarization required for activation. The V
1/2 of inactivation of G1319V channels was shifted by −6.0 mV compared to WT, resulting in a reduced channel availability. The change in the steady-state inactivation was completely due to a negative shift (−6.8 mV) of the voltage-dependence of slow inactivation, while the voltage-dependence of fast inactivation was unaffected. The fast component of recovery from inactivation of G1319V channels was slowed down. Finally, the G1319V mutation caused a two-fold increase in the propensity of the channels to enter the slow inactivated state. Reduction in I
Na peak amplitude on repetitive depolarizations at short interpulse intervals (40 ms) was significantly more pronounced in G1319V compared to WT. Accordingly, carriers of the G1319V mutation showed marked QRS widening upon increases in heart rate during exercise testing, pointing to enhancement of slow inactivation.
Conclusions We identified the DIIIS4-S5 linker as a new region involved in slow inactivation of Nav1.5. The biophysical alterations of the G1319V mutation all contribute to a reduction in I
Na, in line with the proposed mechanism underlying BrS.
Background
One of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono‐allelic mutations in the KCNQ1 gene. Bi‐allelic ...mutations in the KCNQ1 gene are causal to Jervell and Lange‐Nielsen syndrome (JLNS), characterized by severe and early‐onset arrhythmias with prolonged QTc interval on surface ECG and sensorineural deafness. Occasionally, bi‐allelic mutations in KCNQ1 are also found in patients without any deafness, referred to as autosomal recessive long QT syndrome, type 1 (AR LQT1).
Methods
We used Sanger sequencing to detect the pathogenic mutations in KCNQ1 gene in eight families from Saudi Arabia with autosomal recessive LQT1.
Results
We have detected pathogenic mutations in all eight families, two of the mutations are founder mutations, which are c.387‐5T>A and p.Val172Met/p.Arg293Cys (in cis). QTc and cardiac phenotype was found to be pronounced in all the probands comparable to the cardiac phenotype in JLNS patients. Heterozygous carriers for these mutations did not exhibit any clinical phenotype, but a significant number of them have sinus bradycardia.
Conclusion
To the best of our knowledge, this is the first description of a large series of patients with familial autosomal recessive LQT, type 1. These mutations could be used for targeted screening in cardiac arrhythmia patients in Saudi Arabia and in people of Arabic ancestry.
Autosomal recessive long QT syndrome, type 1. Severity of arrhythmia. Bradycardia in nonsymptomatic heterozygous carriers.
Objectives This study was undertaken to determine whether the short-lived sinus tachycardia that occurs during standing will expose changes in the QT interval that are of diagnostic value. Background ...The QT interval shortens during heart rate acceleration, but this response is not instantaneous. We tested whether the transient, sudden sinus tachycardia that occurs during standing would expose abnormal QT interval prolongation in patients with long QT syndrome (LQTS). Methods Patients (68 with LQTS LQT1 46%, LQT2 41%, LQT3 4%, not genotyped 9% and 82 control subjects) underwent a baseline electrocardiogram (ECG) while resting in the supine position and were then asked to get up quickly and stand still during continuous ECG recording. The QT interval was studied at baseline and during maximal sinus tachycardia, maximal QT interval prolongation, and maximal QT interval stretching. Results In response to brisk standing, patients and control subjects responded with similar heart rate acceleration of 28 ± 10 beats/min (p = 0.261). However, the response of the QT interval to this tachycardia differed: on average, the QT interval of controls shortened by 21 ± 19 ms whereas the QT interval of LQTS patients increased by 4 ± 34 ms (p < 0.001). Since the RR interval shortened more than the QT interval, during maximal tachycardia the corrected QT interval increased by 50 ± 30 ms in the control group and by 89 ± 47 ms in the LQTS group (p < 0.001). Receiver-operating characteristic curves showed that the test adds diagnostic value. The response of the QT interval to brisk standing was particularly impaired in patients with LQT2. Conclusions Evaluation of the response of the QT interval to the brisk tachycardia induced by standing provides important information that aids in the diagnosis of LQTS.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease, with male preponderance, characterized by progressive fibrofatty replacement of the right ventricle and ventricular ...arrhythmias. Mutations in plakophilin-2 (PKP2), a desmosomal protein, have been reported to underlie familial ARVC. We report a novel ARVC PKP2 mutation and present the clinical findings in three female mutation carriers.
We sequenced PKP2 from genomic DNA isolated from peripheral blood lymphocytes in a female proband who presented with cardiac arrest and in her four first-degree relatives. Clinical testing and diagnosis of ARVC was based on International Task Force criteria.
The proband was diagnosed with ARVC due to right ventricular enlargement and regional hypokinesis, along with repolarization abnormalities and frequent ventricular ectopy. A novel 28 bp insertion in exon 11 of the PKP2 gene was found which causes a frameshift in the coding region. This results in a change in the amino acid sequence of the protein with a premature stop codon at position 740. Of the four relatives, only the mother and younger sister were identified as mutation carriers. The mother was phenotypically normal, while the younger sister has repolarization abnormalities and frequent ventricular ectopy.
We report a novel PKP2 mutation that causes familial ARVC. All mutation carriers in this kindred group were women, and the family showed incomplete penetrance and variable expression of ARVC. Premature truncation of the plakophilin-2 protein appears to be the predominant mechanism whereby PKP2 mutations elicit the ARVC phenotype.
Extrahepatic complement synthesis is believed to play an important role in host defense and inflammation at tissue and organ level. In the epidermis the most abundant cell type, keratinocytes have ...been shown to produce C3, factor B and factor H. In the present study, we investigated the synthesis of factor I by human keratinocytes. We also studied whether proinflammatory cytokines IL-1α, IL-6, TGF-β1, TNF-α and IFN-γ regulate factor I synthesis in keratinocytes. Human keratinocytes constitutively expressed factor I mRNA and produced factor I protein. Amongst the above-mentioned cytokines, only IFN-γ regulated the synthesis of factor I, and this effect occurred predominantly at pre-translational level. Factor I produced by keratinocytes was functionally active in cleaving C3b. In conclusion, we demonstrate that keratinocytes are capable of synthesizing factor I, and that this synthesis is regulated by IFN-γ.
Primary cardiac arrhythmias are often caused by defects, predominantly in the genes responsible for generation of cardiac electrical potential, i.e., cardiac rhythm generation. Due to the variability ...in underlying genetic defects, type, and location of the mutations and putative modifiers, clinical phenotypes could be moderate to severe, even absent in many individuals. Clinical presentation and severity could be quite variable, syncope, or sudden cardiac death could also be the first and the only manifestation in a patient who had previously no symptoms at all. Despite usual familial occurrence of such cardiac arrhythmias, disease causal genetic defects could also be de novo in significant number of patients. Long QT syndrome (LQTS) is the most eloquently investigated primary cardiac rhythm disorder. A genetic defect can be identified in ∼70% of definitive LQTS patients, followed by Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Brugada syndrome (BrS), where a genetic defect is found in <40% cases. In addition to these widely investigated hereditary arrhythmia syndromes, there remain many other relatively less common arrhythmia syndromes, where researchers also have unraveled the genetic etiology, e.g., short QT syndrome (SQTS), sick sinus syndrome (SSS), cardiac conduction defect (CCD), idiopathic ventricular fibrillation (IVF), early repolarization syndrome (ERS). There exist also various other ill-defined primary cardiac rhythm disorders with strong genetic and familial predisposition. In the present review we will focus on the genetic basis of LQTS and its clinical management. We will also discuss the presently available genetic insight in this context from Saudi Arabia.
Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly syndrome characterized by a distinctive facial appearance, malformations of the upper limbs, and delay in growth and development. ...Mutations in NIPBL are associated with CdLS in 27-56% of cases and have been reported as point mutations, small insertions and deletions in coding regions, regulatory regions and at splice junctions. All previous studies used PCR-based exon-scanning methodologies that do not allow detection of large genomic rearrangements. We studied the relative copy number of NIPBL exons in a series of 50 CdLS probands, negative for NIPBL mutations, by multiplex ligation-dependent probe amplification (MLPA). In a single patient, we found a 5.2 kb deletion encompassing exons 41-42 of NIPBL. Our studies indicate that large NIPBL rearrangements do occur in CdLS but are likely to be infrequent events.
Objectives This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2 -encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT ...interval (QTc). Background Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. Methods Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 ± 15 years, mean QTc 428 ± 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). Results Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. Conclusions Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that ≈65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.
Congenital long QT syndrome (LQTS) is an inherited cardiac arrhythmia disorder characterized by prolongation of the QT interval; patients are predisposed to ventricular tachyarrhythmias and ...fibrillation leading to recurrent syncope or sudden cardiac death. We performed clinical and genetic studies in six Saudi Arabian families with a history of sudden unexplained death of children. Clinical symptoms, ECG phenotypes, and genetic findings led to the diagnosis of LQT1 in two families (recessive) and LQT2 in four families (three recessive and one dominant). Onset of arrhythmia was more severe in the recessive carriers and occurred during early childhood in all recessive LQT1 patients. Arrhythmia originated at the intrauterine stages of life in the recessive LQT2 patients. LQT1, causing mutation c.387-5 T > A in the
KCNQ1
gene, and LQT2, causing mutation c.3208 C > T in the
KCNH2
gene, are presumably founder mutations in the Assir province of Saudi Arabia. Further, all LQTS causing mutations detected in this study are novel and have not been reported in other populations.
IntroductionSudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL. Phenotypes have only begun to be described and no data are available on medical ...therapy after long-term follow-up.MethodsAn international, multicenter retrospective review was conducted. We report new cases associated with TECRL variants and long-term follow-up from previously published cases.ResultsWe present 10 cases and 37 asymptomatic heterozygous carriers. Median age at onset of cardiac symptoms was 8 years (range 1-22 years) and cases were followed for an average of 10.3 years (SD 8.3), right censored by death in 3 cases. All patients on metoprolol, bisoprolol or atenolol were transitioned to nadolol or propranolol due to failure of therapy. Phenotypes typical of both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia were observed. We also observed divergent phenotypes in some cases despite identical homozygous variants. None of 37 heterozygous family members had a cardiac phenotype.ConclusionsPatients with biallelic pathogenic TECRL variants present with variable cardiac arrhythmia phenotypes, including those typical of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Nadolol and propranolol may be superior beta-blockers in this setting. No cardiac disease or sudden death was present in patients with a heterozygous genotype.
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