Regular ArticleA Missense Mutation of Cardiac β-Myosin Heavy Chain Gene Linked to Familial Hypertrophic Cardiomyopathy in Affected Japanese Families
Abstract
A novel missense mutation of the cardiac β-myosin heavy chain gene was detected in five unrelated Japanese patients and their affected family members with hypertrophic cardiomyopathy (HCM) by using the polymerase chain reaction (PCR)-DNA conformation polymorphism (DCP) analysis. Sequencing analysis revealed an A to G transion at codon 778 leading to replacement of the Asp residue, which is adjacent to the interaction sites of myosin heavy chain (MHC) with actin and is a conserved amino acid residue in various MHC across species, to the Gly residue. Linkage study of the mutation and two dinucleotides repeat markers of the cardiac β-MHC gene in three affected families showed that the mutation was on the same haplotype of the cardiac β-MHC gene and linked to HCM. These observations strongly suggest that the 778Asp to Gly mutation is the cause of HCM in these affected individuals.
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Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by an unexplained left ventricular hypertrophy (LVH), usually asymmetrical and involving the interventricular septum. HCM is a relatively frequent disorder, affecting one of 500 individuals from the general population. Some patients may not have any symptoms during their whole life, whereas in other cases, HCM may lead to severe symptoms such as syncope or dyspnea, sudden death, or congestive heart failure. It remains the most prevalent cause of inexplained sudden death in athletes during exercise. HCM is a familial disease in at least 50% of cases, with mainly an autosomal dominant mode of inheritance with variable expression and incomplete penetrance. It may be also inherited in autosomal recessive pattern or X-linked manner. HCM are caused by mutations in nearly 22 different genes, >17 genes are involved in autosomal dominant HCM. The most frequently mutations fall within myosin heavy chain 7 (MYH7) and myosin binding protein C (MYBPC3), both accounting for up to 50% of HCM cases.
The present study reports the molecular results of a series of six unrelated Moroccan patients with HCM using for the first time in Morocco a next generation sequencing (NGS) customized multigene panel to investigate the two major HCM genes MYH7 and MYBPC3. Genetic testing lead to the identification of a novel MYBPC mutation (c.1049delA; p.Lys350fs) and three others previously described variants at heterozygous state.
Molecular diagnosis by NGS customized multigenes panel allowed us to set up a fast and firstline upon request cost-efficient strategy in order to screen various genes and diseases including HCM. This approach is well suited to general medical genetics laboratories dealing with almost all types of rare genetic diseases with limited funds for a molecular testing more cost-effective.
Nucleotide-induced movements in the myosin head near the converter region
2000, Biochimica et Biophysica Acta - Protein Structure and Molecular EnzymologyStructural changes in subfragment 1 of skeletal muscle myosin were investigated by cross-linking trypsin-cleaved S1 with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In the absence of nucleotide the alkali light chains are cross-linked to the 27 kDa heavy chain fragment; the presence of MgATP reduces the efficiency of this reaction. On the other hand, MgATP promotes the cross-link formation between the N-terminal 27 kDa and C-terminal 20 kDa fragments of the heavy chain. The chemical cleavage of the cross-linked heavy chains fragments with N-chlorosuccinimide and hydroxylamine indicates that the cross-links are formed between the regions spanning residues 131–204 and 699–809. These results indicate that the two regions of the heavy chain that are relatively distant in nucleotide-free skeletal S1 [Rayment et al. (1993) Science 261, 50–58] can potentially interact upon addition of nucleotide.
Isometric tension and mutant myosin heavy chain content in single skeletal myofibers from hypertrophic cardiomyopathy patients
1997, Journal of Molecular and Cellular CardiologySeveral mutations in theβ-myosin heavy chain (β-MHC) gene have been linked to hypertrophic cardiomyopathy (HCM). Because this gene is also expressed in slow-twitch fibers of skeletal muscle, we have been able to study the mutantβ-myosin content and mechanical properties associated with these myosin mutations in single skinned skeletal muscle fibers obtained from HCM patients. We found that in patients carrying the 403Arg→Glnmutation, the mutantβ-MHC comprises 47.3±9.1% of the totalβ-MHC present in single slow-twitch fibers. Therefore, both alleles of theβ-MHC gene are on average equally expressed. Isometric tension was decreased by 18% in slow fibers from HCM patients with the 403Arg→Glnmutation, but was unchanged in slow fibers from patients with two otherβ-MHC gene mutations. Taken together with the previous demonstration of reduced velocities generated by these myosins in anin vitroassay, our results suggest that the mutantβ-myosins are functional molecular motors that are able to generate tension and movement, but with abnormal kinetics.
8. Molecular Genetics of Familial Cardiomyopathies
1997, Advances in GeneticsThis chapter reviews the molecular genetics of familial cardiomyopathies. The major cardiomyopathies are hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), and restrictive cardiomyopathy. The chapter focuses on these four disease entities. HCM is defined as a “heart muscle disease of unknown cause” that is characterized by disproportionate hypertrophy of the left ventricle and occasionally also of the right ventricle which typically involves the septum more than the free wall but occasionally is concentric. Dilated cardiomyopathy, which is clinically recognized by uni- or biventricular dilatation, is accompanied by impairment of contractile function, and is associated with rhythm disturbances, thromboembolism, and sudden death. ARVC is characterized by fibro-fatty replacement of the myocardium with a marked predilection for the right ventricle. Initially the disease tends to be patchy, but more diffuse right ventricular involvement, with or without left ventricular abnormalities, may occur later. Clinical features include palpitation, syncope, sudden death, and systolic heart failure. Restrictive cardiomyopathy is probably has the greatest degree of controversy regarding diagnosis and it truly represents a distinct myocardial disorder. It is probable that the majority of cases are the consequence of a nonmyocardial pathological process and thus it is not a primary myocardial disease.
Angiotensinogen gene polymorphism in Japanese patients with hypertrophic cardiomyopathy
1997, American Heart JournalTo examine the contribution of the renin-angiotensin system to hypertrophic cardiomyopathy (HCM), we studied 96 patients with HCM (mean age 50 years, 55% male), 105 of their unaffected siblings and offspring, and 160 healthy subjects without known hypertension and left ventricular hypertrophy (LVH) who were frequency matched to cases by age and sex. Patients were divided into familial or sporadic HCM (FHCM or SHCM) groups with or without affected members of their family. The region of interest in the angiotensinogen (AGT) gene, the missense mutation with methione-to-threonine amino acid substitution at codon 235 in angiotensinogen (M235T), was amplified by polymerase chain reaction with the use of allele-specific oligonucleotide primers flanking the polymorphic region of the AGT gene to amplify template deoxyribonucleic acid prepared from peripheral leukocytes. The T allele frequency was higher in the SHCM group than in unaffected siblings and offspring (88% vs 78%, χ 2= 4.6, p < 0.05). The M allele frequency was higher in unaffected siblings and offspring than in patients with SHCM (23% vs 12%, χ2= 4.6, p < 0.05). The T allele frequency among unaffected siblings and offspring was similar to that observed in healthy subjects (78% vs 78%). We conclude that HCM, especially in sporadic cases, is partially determined by genetic disposition. The molecular variant of angiotensinogen T235 seems to be a predisposing factor for cardiac hypertrophy in HCM and carries an approximately twofold increased risk. (Am Heart J 1997;133:184-9.)
Contractile protein mutations and heart disease
1996, Current Opinion in Cell BiologyMutations in several muscle structural proteins (the myosin heavy chain, α tropomyosin, cardiac troponin T and myosin binding protein C) result in a genetically dominant heart disease, hypertrophic cardiomyopathy. Biochemical data from studies of mutant myosin suggest a dominant—negative mechanism for inheritance of this disease. The most likely primary defect is sarcomere dysfunction, which is followed by the major clinical symptoms.