A new missense mutation, Arg719Gln, in the β-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy

Consevage, Michael W.; Salada, Grant; Baylen, Barry G.; Ladda, Roger L.; Rogan, Peter K.

doi:10.1093/hmg/3.6.1025

Cited by 46 publications

(26 citation statements)

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“…28 In contrast to R719W, R719Q has been associated with nearnormal survival. 15 Nevertheless, the 2 patients found to possess this mutation in the present study have not experienced the natural history ascribed to this mutation: one received an orthotopic heart transplant at the age of 16 years, and the other had a brother who died suddenly at the age of 12 years.…”

Section: Malignant Versus Benign Mutationsmentioning

confidence: 57%

“…Initially, these 8 particular mutations appeared to confer a benign clinical phenotype (ie, near-normal life expectancy) based on a limited number of families: 1 large family with G256E, 12 1 family with F513C, 10 4 families with V606M, 13,14 1 family with R719Q, 15 and 1 family with L908V 19 in MYH7. The S179F-TNNT2 mutation has been reported in a single family, 16 and 3 families were evaluated for the D175N-TPM1 mutation.…”

Section: Malignant Versus Benign Mutationsmentioning

confidence: 99%

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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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Section: Malignant Versus Benign Mutationsmentioning

confidence: 57%

Section: Malignant Versus Benign Mutationsmentioning

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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“…20,21 In MYH7, R403 may be mutated to L, Q, or W; R719 to Q or W; and R663 to S or H. In MYBPC3, R502 may be changed to Q or W and D778 to G or E. In TNNI3, R162 may be mutated to W or P and in MYL2, the residue R58 may be mutated to Q or E.…”

Section: Discussionmentioning

confidence: 99%

Hypertrophic Cardiomyopathy

et al. 2003

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MD; for the EUROGENE Heart Failure ProjectBackground-Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. Methods and Results-The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, and TNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients (Ϸ63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and ␤-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (Pϭ0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. Conclusion-These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened. (Circulation.

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“…The affected family members have a near-normal life expectancy. A699R, K703Q, and K703W are equivalent to G716R, R719Q, and R719W of FHC, respectively (10,14). These FHC mutations exhibit worse prognosis.…”

Section: Introductionmentioning

confidence: 99%

Characterization of mutant myosins of Dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. Molecular force level of mutant myosins may have a prognostic implication.

Fujita¹,

Sugiura²,

Momomura³

et al. 1997

J. Clin. Invest.

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Recent studies have revealed that familial hypertrophic cardiomyopathy (FHC) is caused by missence mutations in myosin heavy chain or other sarcomeric proteins. To investigate the functional impact of FHC mutations in myosin heavy chain, mutants of Dictyostelium discoideum myosin II equivalent to human FHC mutations were generated by site-directed mutagenesis, and their motor function was characterized at the molecular level. These mutants, i.e., R397Q, F506C, G575R, A699R, K703Q, and K703W are respectively equivalent to R403Q, F513C, G584R, G716R, R719Q, and R719W FHC mutants. We measured the force generated by these myosin mutants as well as the sliding velocity and the actin-activated ATPase activity. These measurements showed that the A699R, K703Q, and K703W myosins exhibited unexpectedly weak affinity with actin and the lowest level of force, though their ATPase activity remained rather high.

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A new missense mutation, Arg719Gln, in the β-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy

Cited by 46 publications

References 0 publications

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

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

Hypertrophic Cardiomyopathy

Characterization of mutant myosins of Dictyostelium discoideum equivalent to human familial hypertrophic cardiomyopathy mutants. Molecular force level of mutant myosins may have a prognostic implication.

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