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Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation.

ABSTRACT: Ventricular tachycardia (VT) is a common manifestation of advanced cardiomyopathies. In a subset of patients with dilated cardiomyopathy, VT is the initial and the cardinal manifestation of the disease. The molecular genetic basis of this subset of dilated cardiomyopathy is largely unknown.We identified 10 patients with dilated cardiomyopathy who presented with VT and sequenced 14 common causal genes for cardiomyopathies and arrhythmias. Functional studies included cellular patch clamp, confocal microscopy, and immunoblotting. We identified nonsynonymous variants in 4 patients, including a rare missense p.R397Q mutation in the KCNQ1 gene in a 60-year-old man who presented with incessant VT and had mild cardiac dysfunction. The p.R397Q mutation was absent in an ethnically matched control group, affected a conserved amino acid, and was predicted by multiple algorithms to be pathogenic. Co-expression of the mutant KCNQ1 with its partner unit KCNE1 was associated with reduced tail current density of slowly activating delayed rectifier K(+) current (IKs). The mutation reduced membrane localization of the protein.Dilated cardiomyopathy with an initial presentation of VT may be a forme fruste of arrhythmogenic cardiomyopathy caused by mutations in genes encoding the ion channels. The findings implicate KCNQ1 as a possible causal gene for arrhythmogenic cardiomyopathy.

SUBMITTER: Xiong Q

PROVIDER: S-EPMC4330077 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation.

Xiong Qinmei Q Cao Qing Q Zhou Qiongqiong Q Xie Jinyan J Shen Yang Y Wan Rong R Yu Jianhua J Yan Sujuan S Marian Ali J AJ Hong Kui K

Journal of the American Heart Association 20150123 1

<h4>Background</h4>Ventricular tachycardia (VT) is a common manifestation of advanced cardiomyopathies. In a subset of patients with dilated cardiomyopathy, VT is the initial and the cardinal manifestation of the disease. The molecular genetic basis of this subset of dilated cardiomyopathy is largely unknown.<h4>Methods and results</h4>We identified 10 patients with dilated cardiomyopathy who presented with VT and sequenced 14 common causal genes for cardiomyopathies and arrhythmias. Functional ...[more]

PMID: 25616976

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Project description:Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50% of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis.AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC.Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.

Project description:BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disorder that predominantly affects the right ventricle. Mutations in genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, are the predominant cause of ARVC. A case with novel heterozygous mutation in the LAMA2 gene is reported here. The protein encoded by LAMA2 gene is the α2 chain of laminin-211 protein, which establishes a stable relationship between the muscle fiber membrane and the extracellular matrix. We explored the potential mechanism and the relationship between the mutation and ARVC.Case presentationAt the age of 8, the patient developed syncope and palpitation after exercise. Dynamic electrocardiogram recorded continuous premature ventricular beats, and MRI showed the right ventricle was significantly enlarged and there were many localized distensions at the edge of the right ventricular wall. The patient was diagnosed with ARVC and received heart transplantation at the age of 14 due to severe heart dysfunction. The myocardial histological pathological staining revealed a large amount of fibrosis and adipose migration. Whole exome sequencing (WES) identified the heterozygous mutation in the LAMA2 gene [NM_000426.3: c.8842G > A (p.G2948S)]. This is the first report of these variants. Analysis was performed on genetic disorders to reveal splice site changes and damage to protein structure. LAMA2 p.G2948S predicted unstable protein structure and impaired function. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were established. RNA-seq and the western blot were performed on IPSC-CMs to explore the ARVC-related signaling pathway.ConclusionThis is the first case report to describe an ARVC phenotype in patients possessing a novel LAMA2 c.8842G > A (p.G2948S) mutation. Our results aid in understanding of the pathogenesis of ARVC. The molecular mechanism of LAMA2 leading to ARVC disease still needs further study.

Project description:AimsLikely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.MethodsWe screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant.ResultsForty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants.ConclusionsAlthough PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.

Dataset Information

Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation.

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Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation.

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