Missense mutation of the β‐cardiac myosin heavy‐chain gene in hypertrophic cardiomyopathy

Arai, Shoichi; Matsuoka, Rumiko; Hirayama, Kenji; Sakurai, Hisanao; Tamura, Masaharu; Ozawa, Tenkou; Kimura, Machiko; Imamura, Shinichiro; Furutani, Yoshiyuki; Joh-o, Kunitaka; Kawana, Masatoshi; Takao, Atsuyoshi; Hosoda, Saichi; Momma, Kazuo

doi:10.1002/ajmg.1320580314

Cited by 22 publications

(10 citation statements)

References 26 publications

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“…21,22 At least 50 mutations were found in unrelated families with FHC (Figure 2), and 3 hot spots for mutations were identified, codons 403, 23,32 719, 37,38 and 741. 33,44 All but 3 of these mutations are missense mutations located either in the head or in the head-rod junction of the molecule. The 3 exceptions are two 3-bp deletions that do not disrupt the reading frame, one of codon 10 46 and the other of codon 930, 52 and a 2.4-kb deletion in the 3Ј region.…”

Section: Human Myh7mentioning

confidence: 99%

Familial Hypertrophic Cardiomyopathy

Bonne

Carrier

Richard

et al. 1998

Circulation Research

311

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Abstract-Hypertrophic cardiomyopathy is characterized by left and/or right ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typical morphological changes include myocyte hypertrophy and disarray surrounding the areas of increased loose connective tissue. Arrhythmias and premature sudden deaths are common. Hypertrophic cardiomyopathy is familial in the majority of cases and is transmitted as an autosomal-dominant trait. The results of molecular genetics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes encoding proteins of the myofibrillar apparatus: ␤-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, ␣-tropomyosin, and cardiac myosin binding protein C. In addition to this locus heterogeneity, there is a wide allelic heterogeneity, since numerous mutations have been found in all these genes. The recent development of animal models and of in vitro analyses have allowed a better understanding of the pathophysiological mechanisms associated with familial hypertrophic cardiomyopathy. One can thus tentatively draw the following cascade of events: The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of a "hypocontractile" state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and determine a "hypercontractile" state that would directly induce cardiac hypertrophy. The development of other animal models and of other mechanistic studies linking the genetic mutation to functional defects are now key issues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart. (Circ Res. 1998;83:580-593.)

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Section: Human Myh7mentioning

confidence: 99%

Familial Hypertrophic Cardiomyopathy

Bonne

Carrier

Richard

et al. 1998

Circulation Research

311

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“…According to previous estimates, about 50% of all cases are familial and 50% are sporadic (Maron et al 1987;Greaves et al 1987). Since de novo mutations in HCM-related genes (β-myosin-heavy chain and α-tropomyosin) have been repeatedly identified (Watkins et al 1992(Watkins et al , 1995cGreve et al 1994;Arai et al 1995;Kuang et al 1996;Cuda et al 1996), it is generally believed that sporadic cases also have a genetic basis. Theoretically isolated cases could, in addition, be attributable to recessive mutations, to hypertrophy in the context of unrecognized non-myocardial deficiencies ("secondary" HCM) or to epigenetic or environmental components.…”

Section: Introductionmentioning

confidence: 99%

A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mutated β-myosin heavy chain genes

Jeschke¹,

Uhl²,

Weist³

et al. 1998

Human Genetics

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Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease that is in most cases familial and transmitted in a dominant fashion. The most frequently affected gene codes for the cardiac (ventricular) beta-myosin heavy chain. We have investigated the genetic cause of an isolated case of HCM, which was marked by an extremely severe phenotype and a very early age of onset. HCM is normally not a disease of small children. The proband was a boy who had suffered cardiac arrest at the age of 6.5 years (resuscitation by cardioconversion). Upon screening of the beta-myosin heavy chain gene as a candidate, two missense mutations, one in exon 19 (Arg719Trp) and a second in exon 12 (Met349Thr), were identified. The Arg719Trp mutation was de novo, as it was not found in the parents. In contrast, the Met349Thr mutation was inherited through the maternal grandmother. Six family members were carriers of this mutation but only the proband was clinically affected. Segregation and molecular analysis allowed us to assign the Met349Thr mutation to the maternal and the Arg719Trp de novo mutation to the paternal beta-myosin allele. Thus, the patient has no normal myosin. We interpret these findings in terms of compound heterozygosity of a dominant (Arg719Trp) and a recessive (Met349Thr) mutation. Whereas a single mutated Arg719Trp allele would be sufficient to cause HCM, the concurrent Met349Thr mutation alone does not apparently induce the disease. Nevertheless, it conceivably contributes to the particularly severe phenotype.

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“…The overall genetic diagnostic rate was 72.2% (13/18) and the frequency of disease-causing mutations in the HCM cohort were much higher than previous documentations (22–24), including an American cohort (54.2%), French cohort (60.6%) and Japanese cohort (67%) (25–27). Mutations in the MYBPC3 gene were the most prevalent that were detected in 5 of the 13 patients (38.5%).…”

Section: Discussionmentioning

confidence: 52%

Identification of a novel hypertrophic cardiomyopathy-associated mutation using targeted next-generation sequencing

Zhao

Feng

Ding

et al. 2017

International Journal of Molecular Medicine

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Hypertrophic cardiomyopathy (HCM), one of the most common forms of myocardial diseases, is the major cause of sudden cardiac death in young adults and competitive athletes. Analyses of gene mutations associated with HCM are valuable for its molecular diagnosis, genetic counseling, and management of familial HCM. To dissect the relationship between the clinical presentation and gene mutations of HCM, the genetic characterizations of 19 HCM-related genes in 18 patients (8 cases from 6 pedigrees with familial HCM and 10 cases without familial HCM) were detected using next-generation sequencing (NGS). As a result, 12 disease-related mutations were identified in the 18 subjects, including 6 single mutations and 3 double mutations [MYBPC3 (p.Gln998Glu) plus TNNI3 (p.Arg145Gly), PRKAG2 (p.Gly100Ser) plus MYBPC3 (p.Lys1209Serfs*28) and TNNI3 (p.Glu124Gln) plus GLA (p.Trp47*)]. The 3 heterozygous double mutations were discovered for the first time in the malignant familial HCM patients. Of the 6 single mutations, a novel mutation was found in tafazzin (TAZ, p.Ile208Val), and a mutation in β-myosin heavy chain gene (MYH7, p.Arg54Gln), which was reported as rare in the general population, was firstly found in one HCM patient. Identification of novel and rare mutations in HCM patients have added new data to the spectrum of gene mutations associated with this disease. These findings provide an essential basis for the molecular diagnosis and better management of family members at risk of familial HCM.

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Missense mutation of the β‐cardiac myosin heavy‐chain gene in hypertrophic cardiomyopathy

Cited by 22 publications

References 26 publications

Familial Hypertrophic Cardiomyopathy

Familial Hypertrophic Cardiomyopathy

A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mutated β-myosin heavy chain genes

Identification of a novel hypertrophic cardiomyopathy-associated mutation using targeted next-generation sequencing

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