Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Bashyam, Murali D.; Savithri, Gorinabele R.; Kumar, Murugapiran S; Narasimhan, Calambur; Nallari, Pratibha

doi:10.1007/s100380300007

Cited by 36 publications

(20 citation statements)

References 88 publications

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“…So far, over 500 HCMcausing gene mutations in 10 sarcomeric genes have been described [13]. According to current knowledge, no particular clinical HCM phenotype is mutation-specific, and HCM-causing mutations exhibit highly variable anatomical manifestations on echocardiography [24,25]. To our knowledge, previous CMRI studies on HCM caused by Fig.…”

Section: Discussionmentioning

confidence: 96%

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

et al. 2011

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Section: Discussionmentioning

confidence: 96%

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

et al. 2011

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“…Mutations in ␤-myosin heavy chain (MYH7) cause familial hypertrophic cardiomyopathy (FHC), a leading cause of sudden death in otherwise healthy individuals, 62,63 and dilated cardiomyopathy. 64,65 Interestingly, 17% of these MYH7 mutations lie in the rod of the ␤-myosin heavy chain.…”

Section: Myosin-ii Mutations and Human Pathologymentioning

confidence: 99%

Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly

Franke

Fan

Rickoll

et al. 2005

Blood

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MYH9-related disorders are autosomal dominant syndromes, variably affecting platelet formation, hearing, and kidney function, and result from mutations in the human nonmuscle myosin-IIA heavy chain gene. To understand the mechanisms by which mutations in the rod region disrupt nonmuscle myosin-IIA function, we examined the in vitro behavior of 4 common mutant forms of the rod (R1165C, D1424N, E1841K, and R1933Stop) compared with wild type. We used negative-stain electron microscopy to analyze paracrystal morphology, a model system for the assembly of individual myosin-II molecules into bipolar filaments. Wild-type tail fragments formed ordered paracrystal arrays, whereas mutants formed aberrant aggregates. In mixing experiments, the mutants act dominantly to interfere with the proper assembly of wild type. Using circular dichroism, we find that 2 mutants affect the ␣-helical coiled-coil structure of individual molecules, and 2 mutants disrupt the lateral associations among individual molecules necessary to form higher-order assemblies, helping explain the dominant effects of these mutants. These results demonstrate that the most common mutations in MYH9, lesions in the rod, cause defects in nonmuscle myosin-IIA assembly. Further, the application of these methods to biochemically characterize rod mutations could be extended to other myosins responsible for disease. IntroductionThe autosomal dominant, giant-platelet disorders-May-Hegglin anomaly (MHA), Fechtner (FTNS), Sebastian (SBS), Epstein (EPS), and Alport-like syndromes with macrothrombocytopeniasresult from mutations in the human MYH9 gene, which encodes nonmuscle myosin-IIA heavy chain. [1][2][3][4][5] Virtually all patients exhibit platelet macrocytosis, thrombocytopenia, and leukocyte inclusions. Some individuals also exhibit high-tone sensorineural deafness, cataracts, and nephritis to varying degrees. Additional genetic or environmental factors may contribute to the variable penetrance of the nonhematologic clinical manifestations. 6,7 A single family with predominantly hearing loss has been reported. 8 Together, these illnesses represent a spectrum of disorders collectively termed MYH9-related disorders. 6,7,9 Of the 82 mutations identified in MYH9-related disorder families, only 21 amino acids, out of a possible 1961, are mutated. 3,7,10 Identical MYH9 mutations occur in unrelated families and can arise spontaneously, suggesting that these disorders result from highly specific disruption of the MYH9 structure and/or function. Mutations at other sites may occur and remain undetected owing to (1) a completely recessive alteration in myosin-II function, (2) a weakly penetrant dominant effect that escapes clinical detection, or (3) severe dysfunction that is incompatible with life.In humans, the 3 nonmuscle myosin-II heavy chains (IIA, IIB, and IIC) are encoded by distinct genes (MYH9, MYH10, and MYH14, respectively). 11 Only nonmuscle myosin-IIA is expressed in platelets, 12,13 and no mutations in nonmuscle myosin-IIB or myosin-IIC have been reported. ...

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“…Over 400 causative mutations, most commonly substitutions, have been identified in 20 sarcomere and myofilament related genes [Keren et al, 2008]. The mutations have been observed within 37% (cardiac troponin I) to 91% (cardiac myosin binding protein C) of a gene's exonic regions as opposed to specific hot spots [Bos et al, 2007;Alcalai et al, 2008].In many cases, the mutation is caused by a spontaneously arising, or de novo mutation [Watkins et al, 1992[Watkins et al, , 1995Olson et al, 2000;Marian, 2002;Van Driest et al, 2002.;Bashyam et al, 2003;Marian, 2008].…”

Section: Introductionmentioning

confidence: 97%

“…Hypertrophic cardiomyopathy (HCM) is a common familial form of cardiac disease with clinical manifestations that include the development of congestive heart failure and sudden cardiac death [Bashyam et al, 2003;Marian, 2008]. Over 400 causative mutations, most commonly substitutions, have been identified in 20 sarcomere and myofilament related genes [Keren et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

Differential methylation of CpG sites in two isoforms of myosin binding protein C, an important hypertrophic cardiomyopathy gene

Meurs

Kuan

2010

Environ and Mol Mutagen

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Hypertrophic cardiomyopathy (HCM) is a common form of cardiac disease. Over 400 causative mutations have been identified in 20 sarcomere and myofilament related genes. The high density of mutations found in genes associated with HCM may suggest that mechanisms promoting increased mutability play a role in disease prevalence. The objective of this study was to evaluate the CpG methylation level of the exonic regions of the cardiac myosin binding protein C gene (MYBPC3), a common causal gene for HCM. To determine if the methylation level is gene specific and possibly involved with gene mutability, we also evaluated the methylation of the CpGs within the exonic regions of the skeletal muscle isoform of the myosin binding protein C gene (MYBPC2); there are no known mutations that lead to the development of familial human disease within this gene. We determined that although the mean number of CG sites was identical within the coding region of each gene, the mean methylation level of CpGs was significantly higher in MYBPC3 than MYBPC2 (P < 0.0001). The results of this study suggest that there are unique aspects of this cardiac gene or its epigenetic environment which may result in increased genetic mutability. Evaluation of the methylation levels of additional causal cardiomyopathic genes is warranted.

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Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Cited by 36 publications

References 88 publications

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

Cardiac MRI assessed left ventricular hypertrophy in differentiating hypertensive heart disease from hypertrophic cardiomyopathy attributable to a sarcomeric gene mutation

Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly

Differential methylation of CpG sites in two isoforms of myosin binding protein C, an important hypertrophic cardiomyopathy gene

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