Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family

Hwang, Tae-Hong; Lee, Won‐Ha; Kimura, Akinori; Satoh, Manatsu; Nakamura, Tomohisa; Kim, Myung-Kon; Choi, Suk-Ku; Park, Jeong-Euy

doi:10.1016/s0002-9149(98)00695-x

Cited by 37 publications

(24 citation statements)

References 20 publications

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“…However, it is not simply applicable to all the MYH7 mutations. As shown in Figure 1, three different MYH7 mutations, Arg249Gln, Gly716Arg and Asp778Gly, with poor survival prognosis 14,15 were all categorized into charge altered mutation. On the other hand, there were three other different MYH7 mutations, Arg143Gln, Arg870His and Arg870Cys, with relatively benign survival prognosis 16,17 and two of them, Arg143Gln and Arg870Cys, were also associated with charge alteration.…”

Section: Sarcomere Mutations In Hcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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Section: Sarcomere Mutations In Hcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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“…Erste Befunde in betroffenen Familien deuten darauf hin, dass Mutationen in den Genen der β-Myosin-Schwerkette (MYH7: N232S, G256E, F513C, V606M, R 719Q, L908V), kardialem Troponin T (TNNT2: S179F) und β-Tropomyosin (TPM1: D175N) mit einem eher benignen Krankheitsverlauf mit nahezu normaler Lebenserwartung vergesellschaftet sind [8][9][10][11][12][13][14][15], hingegen ein Teil der sog. malignen Mutationen im MYH7-Gen (R403Q, R453C, G716R, R719W) und im TNNT2-Gen (R92W) mit einer erhöhten Rate von SD und auch rascher Progredienz im Sinne einer schweren Herzinsuffizienz einhergeht [8,10,[16][17][18].…”

Section: Molekulare Analytikunclassified

Hypertrophe Kardiomyopathie

Scheffold¹,

Binner²,

Erdmann³

et al. 2005

Herz

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Hypertrophic cardiomyopathy (HCM) counts as one of primary diseases emanating from the myocardium. In approximately 60% of the cases a familial autosomal dominant trait of disease inheritance was determined. In the majority of the cases a mutation in one of the known 14 disease-causing genes could be proven. With a prevalence of 0.2% HCM is one of the most common genetic heart diseases. The genetic causes, the clinical manifestations as well as the clinical progression are heterogeneous. At present, echocardiography is the most important diagnostic tool. It remains to be seen how the results from magnetic resonance imaging and molecular genetic diagnosis will have impact on the disease management in the future. The prognosis varies according to the localization, the degree of hypertrophy and, in some cases, on the underlying genetic mutation. Sudden death (SD) is a significant risk of the disease in young people. A systematic stratification of patients at a higher risk of SD is desperately needed. The implantation of an AICD is the most effective preventive measure against SD. The basis medication therapy of symptomatic patients uses calcium antagonists or beta-blockers. In high-degree heart failure the typical therapy is applied mainly in combination with beta-blockers and, if indicated, also with antiarrhythmics. When a high degree of outflow obstruction is present, transcoronary ablation of septum hypertrophy (TASH; synonym: percutaneous transluminal septal myocardial ablation [PTSMA]) or myectomy Ercan be performed. Heart transplantion is performed only in very few patients with terminal heart failure. Even though HCM is one of the best-documented genetically based heart diseases, only a few prospective studies and registries have been established, which have produced guidelines and recommendations for diagnostics and therapy. The ACC/ESC Expert Consensus Document is very helpful in this respect. Therefore, there is still a great need for systematic prospective analyses in large patient populations.

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“…Within the ␤-myosin heavy chain gene (MYH7), at least 4 mutations have been ascribed as malignant mutations: R403Q, R453C, G716R, and R719W. 8,10,11 In contrast, 6 particular missense mutations in MYH7 (N232S, G256E, F513C, V606M, R719Q, and L908V), as well as the S179F mutation in troponin T (TNNT2) and the D175N mutation in ␣-tropomyosin (TPM1), have been designated as benign mutations with no increased risk of SCD. 8 -10,12-17 Several studies have reported exceptions to these genotypephenotype correlations [12][13][14]18,19 ; however, the veracity with which the genetic substrate predicts the clinical outcome and the frequency of specific mutations are unknown.…”

mentioning

confidence: 99%

Prevalence and Severity of “Benign” Mutations in the β-Myosin Heavy Chain, Cardiac Troponin T, and α-Tropomyosin Genes in Hypertrophic Cardiomyopathy

et al. 2002

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Background-Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of ␤-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of ␣-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown. Methods and Results-A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. Conclusions-These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course. (Circulation. 2002;106:3085-3090.)

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Early expression of a malignant phenotype of familial hypertrophic cardiomyopathy associated with a Gly716Arg myosin heavy chain mutation in a Korean family

Cited by 37 publications

References 20 publications

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Hypertrophe Kardiomyopathie

Prevalence and Severity of “Benign” Mutations in the β-Myosin Heavy Chain, Cardiac Troponin T, and α-Tropomyosin Genes in Hypertrophic Cardiomyopathy

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