Hypertrophic cardiornyopathy: from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to     

RIG-I has guts： Identification of a role for RIG-I in colitis ：levelopment

Countries in North America and Europe have the highest incidence of inflammatory disorders of the gastrointestinal tract. The prevalence of inflammatory bowel diseases （IBD）, which comprise Crohn＇s disease （CD） and ulcerative colitis （UC）, now ranges from 10-200 cases per 100 000 individuals [ 1 ]. Although new therapeutic approaches have been developed to improve current treatments, the etiology of this disorder remains elusive. Crohn＇s disease and ulcerative colitis are known to show similar clinical and pathological characteristics; however it is now believed that these two forms of IBD are entirely different. Epidemio- logical studies have revealed that these differences might be explained by the fact that environmental and genetic factors play important roles in the pathogenesis and susceptibility to IBD [ 1 ].     

Identification of Risk Pathways and Functional Modules for Coronary Artery Disease Based on Genome-wide SNP Data

Coronary artery disease(CAD) is a complex human disease, involving multiple genes and their nonlinear interactions, which often act in a modular fashion. Genome-wide single nucleotide polymorphism(SNP) profiling provides an effective technique to unravel these underlying genetic interplays or their functional involvements for CAD. This study aimed to identify the susceptible pathways and modules for CAD based on SNP omics. First, the Wellcome Trust Case Control Consortium(WTCCC) SNP datasets of CAD and control samples were used to assess the jointeffect of multiple genetic variants at the pathway level, using logistic kernel machine regression model. Then, an expanded genetic network was constructed by integrating statistical gene–gene interactions involved in these susceptible pathways with their protein–protein interaction(PPI)knowledge. Finally, risk functional modules were identified by decomposition of the network. Of 276 KEGG pathways analyzed, 6 pathways were found to have a significant effect on CAD. Other than glycerolipid metabolism, glycosaminoglycan biosynthesis, and cardiac muscle contraction pathways, three pathways related to other diseases were also revealed, including Alzheimer's disease, non-alcoholic fatty liver disease, and Huntington's disease. A genetic epistatic network of 95 genes was further constructed using the abovementioned integrative approach. Of 10 functional modules derived from the network, 6 have been annotated to phospholipase C activity and cell adhesion molecule binding, which also have known functional involvement in Alzheimer's disease.These findings indicate an overlap of the underlying molecular mechanisms between CAD and Alzheimer's disease, thus providing new insights into the molecular basis for CAD and its molecular relationships with other diseases.     

Generation of ApoE deficient dogs via combination of embryo injection of CRISPR/Cas9 with somatic cell nuclear transfer

正Atherosclerotic cardiovascular disease is the leading cause of death in the world which is resulted from complex interactions among multiple genetic and environmental factors(WHO).Atherosclerosis is a chronic inflammatory disease characterized by accumulation of lipids in the arterial wall(Gofman and Lindgren,1950).Tremendous clinical and experimental efforts have been     

nhe regulation and deregulation of Wnt signaling by PARK genes in health and disease

Wingless/Int （Wnt） signaling pathways are signal transduction mechanisms that have been widely studied In the field of embryogen- esis. Recent work has established a critical role for these pathways in brain development, especially of midbrain dopaminergic neu- rones, However, the fundamental importance of Wnt signaling for the normal function of mature neurones in the adult central nervous system has also lately been demonstrated by an increasing number of studies. Parkinson＇s disease （PD） is the second most prevalent neurodegenerative disease worldwide and is currently incurable. This debilitating disease is characterized by the progres- sive loss of a subset of midbrain dopaminergic neurones in the substontla nigm leadingto typical extrapyramidal motor symptoms. The aetiology of PD is poorly understood but work performed over the Last two decades has identified a growing number of genetic defects that underlie this condition. Herewe review a growing body of data connecting genes implicated in PD--most notablythe PARKgenes-- with Wnt signaling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signaling might be a frequent pathomechanlsm leading to PD. These observations have implications for the patho- genesis and treatment of neurodegenerative diseases in general.     

Mitochondrial mechanism of cardiomyocyte apoptosis induced by stress

Stress induced the serious disorder of cardiac function and cardiovascular diseases. Apoptosis is the cellular basis in stress induced cardiac injury. In our previous study we found that many stressors resulted in mitochondrial damage. It is certain that mitochondria is important mediator in triggering apoptotic cell death, but the mechanism, by which the stress induced mitochondrial injury leads to cardiomyocyte apoptosis, remains unclear. We designed the present study to investigate the changes of the mitochondria in cardiomyocytes undergoing stress and its role in inducing apoptosis. Here we reported that stress changed the membrane fluidity of mitochondria and induced the lipid peroxidation of mitochondrial membrane in     

Identification of sheep ovary genes potentially associated with off-season reproduction

Off-season reproduction is a favorable economic trait for sheep industry.Hu sheep,an indigenous Chinese sheep breed,demonstrates a higher productivity of lambs and displays year-around oestrous behavior under proper nutrition and environment.The genetic basis behind these traits,however,is not well understood.In order to identify genes associated with the off-season reproduction,we constructed a suppression subtractive hybridization(SSH) cDNA library using pooled ovary mRNAs of 6 oestrous Hu females as a tester and the pooled ovary mRNAs of 6 non-oestrous Chinese Merino females as a driver.A total of 382 resulting positive clones were obtained after the SSH.We identified 114 differentially up-regulated genes in oestrous Hu sheep by using subsequent screening and DNA sequencing,of which 8 were previously known,93 were reported for the first time in sheep,and 13 were novel with no significant homology to any sequence in the DNA databases.Functions of the genes identified are related to cell division,signal transduction,structure,metabolism,or cell defense.To validate the results of SSH,6 genes(Ntrk2,Ppap2b,Htra1,Nid1,Serpine2 and Foxola) were selected for conformational analysis using quantitative real-time PCR(qRT-PCR),and two of them(Htral and Foxola) were verified by Northern blot.All of the 6 genes were differentially up-regulated in the ovary of oestrous Hu.It is obvious that off-season reproduction is a complex trait involving multiple genes in multiple organs.This study helps to provide a foundation for the final identification of functional genes involved in the sheep ovary.     

Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins

Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calcium-handling proteins have been implicated in the pathogenesis of HCM. Among these are mutations in TNNC1- encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have each been associated with HCM in multiple studies. In addition, mutations in RYR2-encoded ryanodine receptor 2, CASQ2-encoded calsequestrin 2, CALR3-encoded calreticulin 3, and SRI-encoded sorcin have been associated with HCM, although more studies are required to validate initial findings. While a relatively uncommon cause of HCM, mutations in genes that encode calcium-handling proteins represent an emerging genetic subset of HCM. Furthermore, these naturally occurring disease-associated mutations have provided useful molecular tools for uncovering novel mechanisms of disease pathogenesis, increasing our understanding of basic cardiac physiology, and dissecting important structure-function relationships within these proteins.     

Genetic counselling for hypertrophic cardiomyopathy: are we ready for it?

Hypertrophic cardiomyopathy (HCM) is a dominant genetic disorder of the myocardium associated with dysfunctional contractile proteins. The major risk of HCM is sudden cardiac death, which may occur even in asymptomatic carriers. Causes are highly heterogeneous. Over 140 different mutations in nine sarcomeric genes have been described to date. The majority of cases (80% or more) may eventually be traced to one of these genes. Although genetic counselling is suggested even if mutations are not known, molecular diagnosis implies new options such as carrier identification or - theoretically - preclinical risk stratification. A scheme according to which cardiologists and clinical and molecular geneticists could cooperate in counselling patients and managing HCM clinically is proposed.     

Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients,mouse models and human engineered heart tissue

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction, and a frequent cause of sudden cardiac death at young age. Pharmacological treatment to prevent or reverse HCM is lacking. This may be partly explained by the variety of underlying disease causes. Over 1500 mutations have been associated with HCM, of which the majority reside in genes encoding sarcomere proteins, the cardiac contractile building blocks. Several mutation-mediated disease mechanisms have been identified, with proof for gene- and mutation-specific cellular perturbations. In line with mutation-specific changes in cellular pathology, the response to treatment may depend on the underlying sarcomere gene mutation. In this review, we will discuss evidence for mutation-specific pathology and treatment responses in HCM patients, mouse models and engineered heart tissue. The pros and cons of these experimental models for studying mutation-specific HCM pathology and therapies will be outlined.     

肥厚型心肌病的致病分子机制研究进展

肥厚型心肌病(Hypertrophic cardiomyopathy,HCM)是以左心室及室间隔不对称肥厚为基本特征的原发性心肌病,其发病率约为0.2%,是青少年和运动员心源性猝死的最常见原因。HCM的发病年龄、发病程度和猝死风险等临床表型具有多样性,通常呈常染色体显性遗传。目前已报道的HCM相关突变超过900种,主要定位在β肌球蛋白重链基因、肌球蛋白结合蛋白C基因、心脏肌钙蛋白T基因等13个心脏肌节蛋白基因;另一方面,越来越多的研究显示线粒体基因突变与HCM发生相关。文章在简单介绍HCM形态学特征及临床表型的基础上,着重综述了HCM的致病分子机制及其最新研究进展。     

Hypertrophic cardiomyopathy in daily practice: an introduction on diagnosis,prognosis and treatment

Hypertrophic cardiomyopathy (HCM) is a complex, inherited cardiac disease that has been subject to intense investigation since it was first described in 1957. Over the past 40 years, understanding has evolved regarding the diagnosis, prognosis and treatment of HCM. Analyses of HCM populations from nonreferral centres have refined the insights into the natural history and the occurrence of sudden cardiac death, which is the most devastating component of its natural history. Therapeutic strategies are diverse and may vary during the course of the disease. Optimal therapy depends on symptoms, haemodynamic findings and the presence of risk factors for sudden cardiac death. At present, invasive therapy for patients with obstructive HCM and drug-refractory symptoms includes surgery or percutaneous transluminal septal myocardial ablation.This report summarises the diagnostic criteria, clinical course and therapeutic management of HCM. Attention is also paid to certain issues of special interest in this disease.     

Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23.

Inherited cardiomyopathies may arise from mutations in genes that are normally expressed in both heart and skeletal muscle and therefore may be accompanied by skeletal muscle weakness. Phenotypically, patients with familial dilated cardiomyopathy (FDC) show enlargement of all four chambers of the heart and develop symptoms of congestive heart failure. Inherited cardiomyopathies may also be accompanied by cardiac conduction-system defects that affect the atrioventricular node, resulting in bradycardia. Several different chromosomal regions have been linked with the development of autosomal dominant FDC, but the gene defects in these disorders remain unknown. We now characterize an autosomal dominant disorder involving dilated cardiomyopathy, cardiac conduction-system disease, and adult-onset limb-girdle muscular dystrophy (FDC, conduction disease, and myopathy [FDC-CDM]). Genetic linkage was used to exclude regions of the genome known to be linked to dilated cardiomyopathy and muscular dystrophy phenotypes and to confirm genetic heterogeneity of these disorders. A genomewide scan identified a region on the long arm of chromosome 6 that is significantly associated with the presence of myopathy (D6S262; maximum LOD score [Z(max)] 4.99 at maximum recombination fraction [theta(max)] .00), identifying FDC-CDM as a genetically distinct disease. Haplotype analysis refined the interval containing the genetic defect, to a 3-cM interval between D6S1705 and D6S1656. This haplotype analysis excludes a number of striated muscle-expressed genes present in this region, including laminin alpha2, laminin alpha4, triadin, and phospholamban.     

Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene.

Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy accompanied by myofibrillar disarrays. Molecular genetic analyses have revealed that mutations in 8 different genes cause HCM. Mutations in these disease genes, however, could be found in about half of HCM patients, suggesting that there are other unknown disease gene(s). Because the known disease genes encode sarcomeric proteins expressed in the cardiac muscle, we searched for a disease-associated mutation in the titin gene in 82 HCM patients who had no mutation in the known disease genes. A G to T transversion in codon 740, from CGC to CTC, replacing Arginine with Leucine was found in a patient. This mutation was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha-actitin in the yeast two-hybrid assay. These observations suggest that the titin mutation may cause HCM in this patient via altered affinity to alpha-actinin.     

Disease modeling of desmosome-related cardiomyopathy using induced pluripotent stem cell-derived cardiomyocytes

Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation. Although optimized medical therapies have been developed for heart failure during the last few decades, some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies. Desmosome, which is a dynamic cell-to-cell junctional component, maintains the structural integrity ...     

Familial screening and genetic counselling in hypertrophic cardiomyopathy: the Rotterdam experience

Hypertrophic cardiomyopathy (HCM) is a disease characterised by unexplained left ventricular hypertrophy (LVH) (i.e. LVH in the absence of another cardiac or systemic disease that could produce a similar degree of hypertrophy), electrical instability and sudden death (SD). Germline mutations in genes encoding for sarcomere proteins are found in more than half of the cases of unexplained LVH. The autosomal dominant inherited forms of HCM are characterised by incomplete penetrance and variability in clinical and echocardiographic features, prognosis and therapeutic modalities. The identification of the genetic defect in one of the HCM genes allows accurate presymptomatic detection of mutation carriers in a family. Cardiac evaluation of at-risk relatives enables early diagnosis and identification of those patients at high risk for SD, which can be the first manifestation of the disease in asymptomatic persons. In this article we present our experience with genetic testing and cardiac screening in our HCM population and give an overview of the current literature available on this subject. (Neth Heart J 2007;15:184-9.)