In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of ...the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance.
Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats ...results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes.
We identified a family with DCM carrying a mutation (RBM20(E913K/+)) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20(E913K/+ )carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20(E913K/+ )carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20(E913K/+ )heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment.
A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.
Abstract Background Genetic investigations have established that mutations in proteins of the contractile unit of the myocardium, known as the sarcomere, may be associated with hypertrophic ...cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). It has become clinical practice to offer genetic testing in affected individuals to identify causative mutations, which provides the basis for presymptomatic testing of relatives who are at risk of disease development. This ensures adequate clinical follow-up of mutation carriers, whereas noncarriers can be discharged. However, before genetic testing can be used for individual risk assessment and prediction of prognosis, it is important to investigate if there is a relation between the clinical disease expression (phenotype) of the condition and mutations in specific disease genes (genotype). Methods We reviewed the literature in relation to phenotypic features reported to be associated with mutations in cardiac troponin I (cTnI; TNNI3 ), which is a recognized sarcomeric disease gene in all 3 cardiomyopathies. Results The results of this review did not identify specific genotype-phenotype relations in HCM or DCM, and cTnI appeared to be the most frequent disease gene in RCM. Conclusions To further explore if there is a genotype-phenotype relation, long-term follow-up studies are needed. It is essential to investigate the natural history of the condition among affected individuals and to provide clinical follow-up on disease development among healthy mutation carriers. Such information is required to provide evidence-based counselling for affected families and to elucidate if knowledge about specific genotypes can be used in future risk prediction models.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart muscle disease characterized by structural, electrical, and pathological abnormalities of the right ventricle (RV). Several ...disease loci have been identified. Mutations in desmoplakin have recently been isolated in both autosomal-dominant and autosomal-recessive forms of ARVC. Primary left ventricular (LV) variants of the disease are increasingly recognized. We report on a large family with autosomal-dominant left-sided ARVC.
The proband presented with sudden cardiac death and fibrofatty replacement of the LV myocardium. The family was evaluated. Diagnosis was based on modified diagnostic criteria for ARVC. Seven had inferior and/or lateral T-wave inversion on ECG, LV dilatation, and ventricular arrhythmia, predominantly extrasystoles of LV origin. Three had sustained ventricular tachycardia; 7 had late potentials on signal-averaged ECG. Cardiovascular magnetic resonance imaging in 4 patients revealed wall-motion abnormalities of the RV and patchy, late gadolinium enhancement in the LV, suggestive of fibrosis. Linkage confirmed cosegregation to the desmoplakin intragenic marker D6S2975. A heterozygous, single adenine insertion (2034insA) in the desmoplakin gene was identified in affected individuals only. A frameshift introducing a premature stop codon with truncation of the rod and carboxy terminus of desmoplakin was confirmed by Western blot analysis.
We have described a new dominant mutation in desmoplakin that causes left-sided ARVC, with arrhythmias of LV origin, lateral T-wave inversion, and late gadolinium enhancement in the LV on magnetic resonance images. Truncation of the carboxy terminus of desmoplakin and consequent disruption of intermediate filament binding may account for the predominant LV phenotype.
Aims
Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is ...associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality.
Methods and results
In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender‐specific penetrance of cardiac involvement and major cardiac events. All‐cause mortality of mutation carriers standardized mortality ratio (SMR) was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non‐sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end‐stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All‐cause mortality of mutation carriers was significantly increased SMR 4.0, 95% confidence interval (CI) 2.8–5.2 between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2–4.3).
Conclusions
This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end‐stage heart failure.
Prevalence, Clinical Significance, and Genetic Basis of Hypertrophic Cardiomyopathy With Restrictive Phenotype Toru Kubo, Juan R. Gimeno, Ajay Bahl, Ulla Steffensen, Morten Steffensen, Eyman Osman, ...Rajesh Thaman, Jens Mogensen, Perry M. Elliott, Yoshinori Doi, William J. McKenna We studied the prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy (HCM) with “restrictive phenotype” characterized by restrictive filling and minimal or no left ventricular hypertrophy. Nineteen of 1,226 HCM patients (1.5%) from 16 families had the “restrictive phenotype.” The 5-year survival rate was 56.4%. The “restrictive phenotype” is an uncommon presentation of the clinical spectrum of HCM and is associated with severe limitation and poor prognosis. Mutation analysis for 5 sarcomere genes was feasible in 15 probands, and mutations were found in 8: 4 in beta-myosin heavy chain, and 4 in cardiac troponin I gene.
Dilated cardiomyopathy (DCM), characterized by cardiac dilatation and contractile dysfunction, is a major cause of heart failure.
Inherited DCM can result from mutations in the genes encoding cardiac ...troponin T, troponin C, and α-tropomyosin; different
mutations in the same genes cause hypertrophic cardiomyopathy. To understand how certain mutations lead specifically to DCM,
we have investigated their effect on contractile function by comparing wild-type and mutant recombinant proteins. Because
initial studies on two troponin T mutations have generated conflicting findings, we analyzed all eight published DCM mutations
in troponin T, troponin C, and α-tropomyosin in a range of in vitro assays. Thin filaments, reconstituted with a 1:1 ratio of mutant/wild-type proteins (the likely in vivo ratio), all showed reduced Ca 2+ sensitivity of activation in ATPase and motility assays, and except for one α-tropomyosin mutant showed lower maximum Ca 2+ activation. Incorporation of either of two troponin T mutants in skinned cardiac trabeculae also decreased Ca 2+ sensitivity of force generation. Structure/function considerations imply that the diverse thin filament DCM mutations affect
different aspects of regulatory function yet change contractility in a consistent manner. The DCM mutations depress myofibrillar
function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting
that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.
Idiopathic dilated cardiomyopathy is a common cause of heart failure. Half of cases are believed to be hereditary, and mutations in cardiac sarcomeric contractile protein genes have been reported ...with autosomal dominant inheritance. We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy. We identified a novel TNNI3 mutation in a family with recessive disease. Functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility. TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations.
Objectives The authors sought to investigate the gene and protein expression in Lamin A/C ( LMNA )-mutated dilated cardiolaminopathy (DCM) patients (DCM LMNA Mut ) versus LMNA -wild-type DCM (DCM ...LMNA WT ), and normal controls (CTRL LMNA WT ). Background Dilated cardiolaminopathies are clinically characterized by high arrhythmogenic risk and caused by LMNA mutations. Little is known regarding quantitative gene expression (QGE) of the LMNA gene in blood and myocardium, as well as regarding myocardial expression of the lamin A/C protein. Methods Using the comparative ΔΔCT method, we evaluated the QGE of LMNA (QGE LMNA ) in peripheral blood and myocardial RNA from carriers of LMNA mutations, versus blood and myocardial samples from DCM LMNA WT patients and CTRL LMNA WT individuals. After generating reference values in normal controls, QGE LMNA was performed in 311 consecutive patients and relatives, blind to genotype, to assess the predictive value of QGE LMNA for the identification of mutation carriers. In parallel, Lamin A/C was investigated in myocardial samples from DCM LMNA Mut versus DCM LMNA WT versus normal hearts (CTRL LMNA WT ). Results LMNA was significantly underexpressed in mRNA from peripheral blood and myocardium of DCM LMNA Mut patients versus DCM LMNA WT and CTRL LMNA WT . In 311 individuals, blind to genotype, the QGE LMNA showed 100% sensitivity and 87% specificity as a predictor of LMNA mutations. The receiver-operating characteristic curve analysis yielded an area under the curve of 0.957 (p < 0.001). Loss of protein in cardiomyocytes' nuclei was documented in DCM LMNA Mut patients. Conclusions The reduced expression of LMNA gene in blood is a novel potential predictive biomarker for dilated cardiolaminopathies with parallel loss of protein expression in cardiomyocyte nuclei.
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