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Familial hypertrophic cardiomyopathy responsible gene mapping and pathogenesis Heart Journal 2000, Volume 12, No. 1 Summary of the article: Li Zhili Published : Keywords: Hereditary disease; hypertrophic cardiomyopathy
Abstract Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disease, single-mutant alleles to disease liability. Over the past decade using microsatellite genetic markers in the disease found in family responsibilities 7 disease gene, pathogenic mechanisms, "peptide agents" and "null allele" two theories. Location of the responsible gene, myofibrillar section pathogenesis of mutant proteins produced an overand analysis of genotype with its phenotype, in order to facilitate the diagnosis and treatment.
CLC number: R596.1; R542.2 Document code: A Article ID :1005 -3271 (2000) 01-0050-03
Familial hypertrophic cardiomyopathy (FHCM) is cardiac hypertrophy, pathological hypertrophy of cardiac muscle fibers, characterized by disordered genetic disease, the Department of autosomal dominant inheritance, a single mutant alleles to disease liability. Hypertrophic cardiomyopathy accounts for about 80% have different clinical phenotype, patients may have difficulty breathing, palpitations, dizziness and other symptoms, severe cases can cause heart failure, shock and sudden death, there are a few healthy young man to death as the only performance. Annual death rate of about 3% to 5%. Explicit and age-related diseases, a small number of mutati


ons in the gene family members were nothing more than disease can be life-long. It is because of FHCM phenotype diversity and a degree of unpredictability of the current lack of clinical HCM sensitive diagnostic criteria. The past decade, the discovery of disease genes responsible, so we FHCM etiology, pathogenesis, diagnosis and treatment of a new understanding.The late 80s, SSLPs technology and genetic linkage analysis of software development, many genetic diseases pedigree DNA loci to specific chromosomes, followed by disease genes found. To date, nine different chromosomes FHCM the DNA sites were found and identified seven different responsibilities genes [1 5]. Be pointed out that a FHCM and pre-excitation syndrome (WPW) with pedigrees, DNA loci on the long arm of chromosome 7 in Area 3 (7q3) [6]; another apical hypertrophic cardiomyopathy (FAHCM) and WPW With pedigrees DNA loci 9p13.2-q13.2, has not found a disease gene [5] (see Table 1).No. disease sites of chromosomal DNA gene and protein names found time positioning of myofibrillar Festival5 FHCM 12q23-24.3 regulating myosin light chain (MRLC) 1996 [3] thick wire
6 FHCM 11p11.2 myosin binding protein C (MyBPC) 1996 [4] C, thick wire
7 FHCM 19p13.2-q13.2 troponin inhibitory subunit (TnI) 1997 [5] filaments
8 FHCM WPW 7q3?? [6]?
9 FAHCM WPW 19p13.2-q13.2?? [5]?
2 genotype and phenotype relationship between the concept of a gene to a 2.1 site on the DNA of the two alleles determine the individual's genotype, that is, if a gene has n pairs of alleles, there may be n (n 1) / 2 genotype. Locus of any DNA mutations are likely to form abnormal genotype. Phenotype is observed in the expression of a gene with any biochemical, cellular, or clinical characteristics, genotypes than phenotypes. Disease penetrance means that when carrying a disease gene, the patient has a gene phenotype (positive characteristics or laboratory results) of the percentage.
2.2 FHCM genotype -MHC is the first causative gene identified FHCM, has reported more than 40 missense mutations, only a single amino acid protein that is replaced; only missense mutation found in there: - Tm 3 (Ala63Val, Asp175Asn, Glu180Gly) [2,10]; MELC 2 (Arg154His, Met149Val); MRLC 3 (Glu22Lys, Ala13Thr, Pro94Arg); TnT 2 (Arg145Gly, Lys206Gln). It is interesting to TnT, MyBPC addition to 7, respectively, 5 missense mutations, there are deletion, insertion, and duplication mutations can occur early termination of expressed sequence code, resulting in the corresponding truncated protein. Currently only 1 case reported by TnT intr5 donor sites G1 A mutation, the ex5 deletion (39 bp), produced truncated TnT. Truncated mutant protein causes MyBPC 9 cases: 791 into the G, 955 missing CT [7], intron 30 donor sites G5 C mutations in exon 30 deletion (140 bp) [8], intron 20 acceptor site A2 G mutations in exon 21 after missing (160 bp) and so on.
Based on available information, Hugh and other estimates of different mutations leading to FHCM proportion, -MHC was 30% ~ 40%, TnT and MyBPC each for 15%, -Tm of about 5%, MELC, and less than 1 MRLC % and the remaining 25% to 35% of the gene.
2.3 mutant genotype and phenotype relationship FHCM patients have different clinical manifestations, such as cardiac hypertrophy, sudden death probability, life span and so on. Allelic heterogeneity (multiple mutations in the same gene may be a separate disease) and non-allelic heterogeneity (multiple genes may be a separate disease) could explain these different phenotypes. First of all, between the different mutations, clinical manifestations may have a more significant differences. Although only moderate in patients with TnT mutations, or even no significant cardiac hypertrophy, but lower than -MHC mutations in patients with a greater risk of sudden death and poor prognosis; MyBPC onset of age-related mutations, disease penetrance is not complete and the prognosis is good; The inhibitory subunit (TnI) mutation is manifested in patients with apical hypertrophy; MELC mutation showed the middle left ventricle hypertrophy, severe cardiac contraction, far into the left ventricle, the proximal two cavity; Although MRLC mutant who have similar changes, but the disease penetrance is low. In addition, -MHC has proved different disease mutations in exons have different rates and survival [9]. Some people tried to change the hypothesis to explain the charge of different -MHC mutations in clinical performance, but Arg430GLu mutations in patients with 45% mortality rate at age 45, and with the same charge to change the Arg430Trp risk of sudden death in patients with small [10], so far, yet not clear genotype (particularly alleles heterogeneous genotype) and the corresponding relationship between the clinical manifestations of a particular gene mutation phenotype still has a considerable degree of unpredictability.Details still unclear FHCM pathogenic mechanism, but there are two theories: abnormal protein gene mutation as "peptide agents" interfere with the normal function of proteins, known as the "dominant negative effect. [11]. mutant gene as a "null allele" can not be expressed or expressed protein instability, the structure can not be mixed with filaments, resulting in a lack of absolute number of structural proteins [12]. Most scholars support the "poison peptide" theory, the following in accordance with the mutant gene expressed in the sarcomere structure and function of proteins were described pathogenic mechanism.
3.1 by a pair of myosin heavy chain myosin, light chain and the need to adjust the composition of the light chain gene co-expression. -MHC is the head of the rod with a spherical structure, heart muscle myosin globular head of the three-dimensional structure is not clear. Found -MHC missense mutations are more concentrated near the head of the five areas [13], one of the molecular binding region and MELC connected. Tohtong [14] found that mutations in transgenic Drosophila MRLC reaction could be the loss of muscle fiber activation; in vitro, -MHC Arg403Gln missense mutation in the skeletal muscle expression, the proof of purified myosin filament sliding speed is reduced 80%, reducing the energy output [15]. Straceski reported [16] unc54 MHC missense mutation in the gene expression of C. elegans to a stable polypeptide, and myofilament incorporation of the structure can interfere with the normal section of myofibril assembly, which is supported by "peptide agents" strong evidence of the hypothesis. The problem is that Nishi et al [17] reported a Japanese family of 16-year-old boy while a missense mutation and a nonsense mutation; boys father Department FHCM only missense mutation in patients; and her mother and grandmother is not suffering from FHCM, only nonsense mutations. Speculated that pathogenic missense mutation, nonsense mutation results from a recessive gene phenotype.
3.2 Troponin consists of 3 sub-units, namely, myosin binding subunit (TnT), calcium binding subunit (TnC), inhibitory subunit (TnI). Filaments in the sarcomere in troponin and Tm and actin together form the hinge-like structure [18]. Currently found in Tm, TnI, and the small number of mutations are missense mutations, not in-depth study of its pathogenic mechanism. However, Watkins et al [19] reported that the TnT can produce truncated protein intr5 donor sites G1 A mutation, the cloning of the mutated cDNA of the CMV vector can into myocardial cells in the quail - myotubes system expressed by filament antibody staining and found that truncated protein aggregation in myotubes, followed by mixing myofibrils section, and protein function in vitro studies have shown that truncated proteins of the calcium-activated contraction was significantly reduced. The results also support the "poison peptide" hypothesis. Unfortunately, the mutation FHCM patients without myocardial biopsy to obtain evidence of truncated proteins.
3.3 myosin structure C is highly cell immunoglobulin super family of a member of the molecular weight of 141 KD, structural proteins and regulatory proteins with dual functions. Isoforms in heart tissue MyBPC not other tissues. Total protein 10 function areas, 10 areas with the myosin binding, 8 to 10 areas together with the muscle proteins (Titin) with [20], when the mutation MyBPC truncated protein, it is easy to change or all of the lost most end of the 8 to 10 areas, causing damage to the structure and function, so most scholars must "peptide agents" mechanism. Surprisingly, in 1997 Rottbauer [8] for the position of intron 31 points G1 A mutation in patients with myocardial biopsy FHCM family, protein identification using MyBPC antibodies, the results did not find expected truncated protein (sensitivity when the cut-off short amount of protein in the normal protein can be detected in 1.5%). This is undoubtedly the "poison peptide" mechanism to challenge. So to clear pathogenic mechanism of myocardial expression of depth MyBPC more animal experiments and biopsy in patients with clinical evidence of cardiac abnormal protein is particularly important.
4 FHCM gene diagnosis, treatment prospects
And linkage analysis using SSLPs, the first 9 months from the known chromosomal DNA loci identified in the candidate gene family tested, and then determined the nucleotide sequences identified genotype, accurate diagnosis is a qualitative method. 7 different mutations have clinical features between the differences in disease genes contribute to rapid screening. At the same time, allow us to clearly determine the genotype in patients with positive family, in particular, the disease has not yet explicit focus on care of patients, to effectively prevent and control purposes.
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