家族性肥厚型心肌病与心肌β肌球蛋白重链基因突变

家族性肥厚型心肌病(FHCM)的发病机理尚不清楚,近年来有研究认为FHCM与心肌β肌球蛋白重链(βMHC)基因突变有关,其中βMHC基因第1294和1443位点突变意义较大,本文对此作一介绍和评述。     

心脏肌球蛋白结合蛋白C基因G4295A突变与中国家族性肥厚型心肌病临床表型的关系

目的 研究中国人家族性肥厚型心肌病（HCM）的致病基因突变位点,分析基因型与临床表型的相互关系。方法 在100例肥厚型心肌病患者以及120例健康对照者中进行心脏型肌球蛋白结合蛋白C基因（MYBPC3）突变筛查,聚合酶链式反应（PCR）扩增基因功能区外显子片段并对PCR产物进行测序分析。结果 在2例HCM（ZHQ和JXW）患者中发现MYBPC3基因第6号外显子第4295位碱基由G转换为A,结果导致第258位的谷氨酸（Glu, E）转变为赖氨酸（Lys, K）,正常对照组相同位置未发现异常。对这2例先证者进行家系调查发现ZHQ和JXW家族受调查者中分别还有2名和1名成员携带该突变,但均未发病。结论 MYBPC3基因为我国家族性 HCM的致病基因之一,E258K突变所致肥厚型心肌病表型呈现外显率较低且临床症状相对较轻的特点。     

新疆3个HCM家系MYH7基因突变DHPLC检测和DNA测序结果分析

目的 研究家族性肥厚型心肌病(HCM)的主要致病基因β肌球蛋白重链,MYH7突变情况.方法 用变性高效液相色谱DHPLC检测和DNA测序方法对3个HCM家系成员的MYH7基因8、14外显子及附近上下游序列进行检测分析.结果 3个家系其中1个家系发现MYH7基因14外显子中存在Thr441Met突变,该突变在中国人中是首次发现,此外外显子8也存在1个点突变.另外两个家系也发现有不同位点的突变.结论 运用变性高效液相色谱技术和DNA直接测序技术能实现对家族性肥厚型心肌病MYH7基因突变的筛查,有利于早期诊断、患病风险预测.     

肥厚型心肌病分子遗传学研究进展

肥厚型心肌病(hypertrophic cardiomyopathy,HCM)是一种以常染色体显性遗传为特征的具有遗传异质性的心脏疾病,它是年轻人心源性猝死的首要病因。已发现至少有18种基因的突变可导致家族性肥厚型心肌病,加深对其分子遗传学的认识有利于促进该病的诊断和治疗。现就家族性肥厚型心肌病近期分子遗传学的研究进行了总结。     

家族性肥厚型心肌型与心肌β肌球蛋白重链基因突变

家族性肥厚型心肌病（ＦＨＣＭ）的发病机理尚不清楚，近年来有研究认为ＦＨＣＭ与心肌β肌球蛋白重链（βＭＨＣ）基因突变有关，其中βＭＨＣ基因第１２９４和１４４３位点突变意义较大，本文对此作一介绍和评述。     

1995WHO/ISFC对心肌病的定义和分类

心肌病是指伴有心功能障碍的心肌疾病．过去心肌病的定义是：原发性（病因未明）心肌病（Cardiomyopathy）,包括扩张型心肌病、肥厚性心肌病、限制型心肌病、致心律失常性右室心肌病和未分类心肌病．另一类是特异性（已知病因）心肌疾病（Specifieheartmuscledisease）．随着对其病因和发病机制的渐多了解,两类的区别渐减少．目前心肌病的分类主要是根据病理生理,病因学和发病因素来认识的．定义和分类心肌病是伴有心功能减损的心肌疾病,它们分为扩张型心肌病、肥厚型心肌病．限制型心肌病和致心律失常右室心肌病．扩张型心肌病扩张型…     

肥厚性心肌病的分子基础与临床意义

肥厚性心肌病是一种遗传异质性疾病。第一个肥厚性心肌病基因位点于１９８９年定位于第１４号染色体长臂的β型肌球蛋白重链基因。迄今已有３０多个点突变和一个缺失突变被发现。带突变的ｍＲＮＡ和蛋白质表达在肥厚性心肌病病人的心肌和骨骼肌。除β型肌球蛋白重链基因外，最近又有３个基因位点被发现，分别位于第１、１１和１５号染色体的长臂。其确切基因尚在探索中。临床分析表明，某些基因突变与心脏猝死的高发率有关。筛查基因突变具有重要临床意义。     

肥厚性心肌病的分子基础与临床意义

肥厚性心肌病是一种遗传异质性疾病。第一个肥厚性心肌病因位点于１９８９年定位于第１４号染色体长臂的β型肌球蛋白重链基因，迄今已有３０多个点突变和一个缺失突变被发现。带突变的ｍＲＮＡ和蛋白质表达在肥厚性心肌病病人的心肌和骨骼肌。除β型肌球蛋白重链基因外，最近又有３个基因位点被发现。分别位于第１、１１和１５号染色体的长臂，其确切基因尚在探索中，临床分析表明，某些基因突变与心脏猝死的高发率有关。筛查基因突     

家族性肥厚型心肌病易感基因与HLA-DQ位点相关性分析

本文报道应用ＰＣＲ／ＳＳＯ方法分析了４个无肌凝蛋白重链基因突变的肥厚型心肌病多发家系成员ＨＬＡ－ＤＱ基因多态性，进行患病同胞共享ＨＬＡＤＱＡ１／ＤＱＢ１单倍型分析和Ｌｏｄｓ分析。结果表明，本病的易感基因与ＨＬＡ－ＤＱ基因存在连锁关系。提示在ＨＬＡ－ＤＱ座位附近可能存在与家族性肥厚型心肌病易感性有关的致病基因。     

家族性肥厚型心肌病易感基因与HLA—DQ位点相关性…

本文报道应用ＰＣＲ／ＳＳＯ方法分析了４个无肌凝蛋白重链基因突变的肥厚型心肌病多发家系成员ＨＬＡ－ＤＱ基因多态性，进行患病同胞共享ＨＬＡ ＤＱＡ１／ＤＱＢ１单倍型分析和Ｌｏｄｓ分析，结果表明，本病的易感基因与ＨＬＡ－ＤＱ基因存在连锁关系，提示在ＨＬＡ－ＤＱ座位附近可能存在与家族性肥厚型心肌病易感性有关的致病基因。     

Familial hypertrophic cardiomyopathy: genes, mutations and animal models. A review

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, which may afflict as many as 1 in 500 subjects (0.2%), being probably the most common hereditary cardiovascular disease and the most common cause of sudden cardiac death (SCD). Hypertrophic cardiomyopathy is characterized by the presence of unexplained left ventricular hypertrophy (in absence of hypertension, valvular disease, etc), which is usually asymmetric and involves the ventricular septum. Molecular genetic studies have identified eleven genes that code proteins of the sarcomere that are associated with the HCM; the beta-myosin heavy chain gene (MYH7), alpha-myosin heavy chain (MYH6), cardiac troponin T (TNNT2); cardiac troponin C (TNNC1), alpha-tropomyosin (TPM1), myosin binding protein-C (MYBPC3), cardiac troponin (TNNI3), essential and regulatory light chain genes (MYL3 and MYL2, respectively), cardiac alpha-actin gene (ACTC) and titin (TTN). The objective of this paper is the revision of the current state of the knowledge on (1) the organization and mutations of the HCM causing genes and their proteins and (2) the animal models developed for the study of the genes, mutations and proteins in the hypertrophic cardiomyopathy.     

A rapid protocol for cardiac troponin T gene mutation detection in familial hypertrophic cardiomyopathy

Mutations in the human cardiac troponin T gene (TNNT2) are associated with familial hypertrophic cardiomyopathy (FHC) linked to chromosome 1q3 (CMH2). Mutation analyses of TNNT2 have been restricted to RNA-based screening methods because only the TNNT2 cDNA sequence was known. We characterized the genomic structure of 15 TNNT2 exons spliced into the adult isoform. A protocol for rapid mutation detection based on direct sequencing of large PCR-amplified genomic DNA fragments revealed a known TNNT2 mutation (Phe110Ile) in one of 30 FHC probands. Three polymorphic short tandem repeat elements (D1S477, D1S2622, and D1S1723), useful for FHC pedigree analyses at CMH2, were shown to be physically tightly linked to TNNT2. Hum Mutat 11:179–182, 1998. © 1998 Wiley-Liss, Inc.     

Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy

Defects in nine sarcomeric protein genes are known to cause hypertrophic cardiomyopathy (HCM). Mutation types and frequencies in large cohorts of consecutive and unrelated patients have not yet been determined. We, therefore, screened HCM patients for mutations in six sarcomeric genes: myosin-binding protein C3 (MYBPC3), MYH7, cardiac troponin T (TNNT2), alpha-tropomyosin (TPM1), cardiac troponin I (TNNI3), and cardiac troponin C (TNNC1). HCM was diagnosed in 108 consecutive patients by echocardiography (septum >15 mm, septal/posterior wall >1.3 mm), angiography, or based on a state after myectomy. Single-strand conformation polymorphism analysis was used for mutation screening, followed by DNA-sequencing. A total of 34 different mutations were identified in 108 patients: 18 mutations in MYBPC3 in 20 patients [intervening sequence (intron) 7 + 1G > A and Q1233X were found twice], 13 missense mutations in MYH7 in 14 patients (R807H was found twice), and one amino acid change in TPM1, TNNT2, and TNNI3, respectively. No disease-causing mutation was found in TNNC1. Cosegregation with the HCM phenotype could be demonstrated for 13 mutations (eight mutations in MYBPC3 and five mutations in MYH7). Twenty-eight of the 37 mutation carriers (76%) reported a positive family history with at least one affected first-grade relative; only eight mutations occurred sporadically (22%). MYBPC3 was the gene that most frequently caused HCM in our population. Systematic mutation screening in large samples of HCM patients leads to a genetic diagnosis in about 30% of unrelated index patients and in about 57% of patients with a positive family history.     

Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology

We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.     

Localization of the fast skeletal muscle troponin I gene (TNNI2) to 11p15.5: genes for troponin I and T are organized in pairs

We have localized the gene encoding the fast skeletal muscle isoform of troponin I (TNNI2) to 11p15.5 by PCR-based analysis of somatic cell hybrid panels: based on the Genebridge4 radiation hybrid panel, TNNI2 is coincident with the marker D11S922. The gene encoding the fast skeletal muscle troponin T gene (TNNT3) has been previously assigned to 11p15.5 suggesting that TNNI2 and TNNT3 may be closely linked. The overall location of genes encoding troponin I and T isoforms now reveals that they are organized at three loci each containing a troponin I/troponin T gene pair. This organization contrasts with all other sarcomeric protein genes and has implications for the evolution of these two gene families, for their regulation and for the analysis of mutations suspected to result in cardiomyopathy.     

Troponin T: genetics, properties and function

Troponin T (TnT) is present in striated muscle of vertebrates and invertebrates as a group of homologous proteins with molecular weights usually in the 31–36kDa range. It occupies a unique role in the regulatory protein system in that it interacts with TnC and TnI of the troponin complex and the proteins of the myofibrillar thin filament, tropomyosin and actin. In the myofibril the molecule is about 18nm long and for much its length interacts with tropomyosin. The ability of TnT to form a complex with tropomyosin is responsible for locating the troponin complex with a periodicity of 38.5nm along the thin filament of the myofibril. In addition to its structural role, TnT has the important function of transforming the TnI–TnC complex into a system, the inhibitory activity of which, on the tropomyosin–actomyosin MgATPase of the myofibril, becomes sensitive to calcium ions. Different genes control the expression of TnT in fast skeletal, slow skeletal and cardiac muscles. In all muscles, and particularly in fast skeletal, alternative splicing of mRNA produces a series of isoforms in a developmentally regulated manner. In consequence TnT exists in many more isoforms than any of the other thin filament proteins, the TnT superfamily. Despite the general homology of TnT isoforms, this alternative splicing leads to variable regions close to the N-and C-termini. As the isoforms have slightly different effects on the calcium sensitivity of the actomyosin MgATPase, modulation of the contractile response to calcium can occur during development and in different muscle types. TnT has recently aroused clinical interest in its potential for detecting myocardial damage and the association of mutations in the cardiac isoform with hypertrophic cardiomyopathy.This revised version was published online in September 2005 with corrections to the Cover Date.     

Cardiomyopathy in congenital complete lipodystrophy

Molecular genetic studies have pointed to a relationship between congenital lipodystrophy syndromes and some cardiac disorders. For instance, mutations in LMNA cause either lipodystrophy or cardiomyopathy, indicating that different mutations in the same gene can produce these clinical syndromes. The present authors describe a 10-year-old female with Berardinelli-Seip congenital complete lipodystrophy (MIM 606158) caused by homozygosity for a frameshift mutation in BSCL2. In addition to the typical attributes of complete lipodystrophy, this subject had hypertrophic cardiomyopathy diagnosed in the first year of her life; its progress has been followed with non-invasive imaging. The mechanism underlying the hypertrophic cardiomyopathy in complete lipodystrophy is unclear. It may result from a direct effect of the mutant gene or it might be secondary to the effects of hyperinsulinemia on cardiac development. The variability of the associated cardiomyopathy in patients with complete generalized lipodystrophy may be caused by differential effects of mutations in the same gene or of mutations in different genes which underlie the lipodystrophy phenotype.     

Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy.

BACKGROUND. Familial hypertrophic cardiomyopathy is characterized by a variable degree of myocardial hypertrophy and a wide range of symptoms. Different mutations in the beta cardiac myosin heavy-chain gene have been identified in three affected families. However, neither the proportion of cases attributable to myosin mutations nor the effects of different mutations on clinical outcome are known. METHODS. Using a ribonuclease protection assay, we screened the beta cardiac myosin heavy-chain genes of probands from 25 unrelated families with familial hypertrophic cardiomyopathy; this assay is a sensitive method for detecting the presence and location of mutations. We further defined the mutations by analyzing their nucleotide sequences. The clinical features of the disease were compared in families with various myosin mutations. RESULTS. Seven mutations in the beta cardiac myosin heavy-chain gene were identified in 12 of the 25 families. All were missense mutations (i.e., causing the substitution of a single amino acid) clustered in the head and head-rod junction regions of the molecule. Six mutations resulted in a change in the charge of the amino acid. Patients with mutations that changed the charge of the altered amino acid (such as that from arginine to glutamine at nucleotide 403 or from arginine to cysteine at nucleotide 453) had a significantly shorter life expectancy (mean age at death, 33 years), whereas patients with the one mutation that did not produce a change in charge (Val606Met) had nearly normal survival. However, patients with different mutations did not differ appreciably in their clinical manifestations of familial hypertrophic cardiomyopathy. CONCLUSIONS. Different missense mutations in the beta cardiac myosin heavy-chain gene can be identified in approximately 50 percent of families with hypertrophic cardiomyopathy. In those families, a definite genetic diagnosis can be made in all members. Since the location of a mutation or its DNA-sequence alteration (or both) appears to influence survival, we suggest that the precise definition of the disease-causing mutation can provide important prognostic information about affected members.