Homozygotes for a R869G Mutation in the β -myosin Heavy Chain Gene have a Severe Form of Familial Hypertrophic Cardiomyopathy

Richard, Pascale; Charron, Philippe; Leclercq, Christophe; Ledeuil, C.; Carrier, Lucie; Dubourg, Olivier; Desnos, Michel; Bouhour, J B; Schwartz, Ketty; Daubert, Jean Claude; Komajda, Michel; Hainque, Bernard

doi:10.1006/jmcc.2000.1193

Cited by 56 publications

(23 citation statements)

References 31 publications

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“…The homozygote and double-heterozygote patients in this and other reports have a clinical course characterized by either severe LV hypertrophy (21,27) and/or progressive LV systolic dysfunction, severe LA enlargement, and AF (18,25,26), suggesting a gene-dose effect on the severity of phenotypic expression. The phenotypic progression to LV dilatation and systolic impairment is relatively uncommon, described in only ϳ10% of FHC patients (16,30).…”

Section: Discussionsupporting

confidence: 51%

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

Alpert¹,

Mohiddin²,

Tripodi³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations. Am J Physiol Heart Circ Physiol 288: H1097-H1102, 2005. First published November 4, 2004 doi:10.1152/ajpheart.00650.2004.-Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding ␤-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V actin) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V actin was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V actin for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V actin may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.

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Section: Discussionsupporting

confidence: 51%

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

Alpert¹,

Mohiddin²,

Tripodi³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…Group 3 included 3 families with homozygous mutated patients. Two of them were mutated in MYH7 (one with the R869G mutation 13 and the other with the D778E mutation) and one in MYBPC3 (Q76ter). Phenotype-genotype analyses of these families are summarized in Table 6.…”

Section: Resultsmentioning

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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“…3 Alternatively, children with familial HCM may have more severe disease than their adult relatives because of a second inherited or de novo mutation, resulting in compound heterozygosity 4 or homozygosity. [5][6][7] We studied a family with recessive HCM to determine if an inherited sarcomeric protein defect could be clinically silent in the heterozygous state, causing HCM only in the presence of 2 mutant alleles.…”

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Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology

et al. 2002

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Background-Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. Methods and Results-We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism. Conclusions-Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.

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Homozygotes for a R869G Mutation in the β -myosin Heavy Chain Gene have a Severe Form of Familial Hypertrophic Cardiomyopathy

Cited by 56 publications

References 31 publications

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

Hypertrophic Cardiomyopathy

Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology

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