Possible Gene Effect of a Mutant Cardiac β-Myosin Heavy Chain Gene on the Clinical Expression of Familial Hypertrophic Cardiomyopathy

doi:10.1006/bbrc.1994.1483

Biochemical and Biophysical Research Communications

Volume 200, Issue 1, 15 April 1994, Pages 549-556

https://doi.org/10.1006/bbrc.1994.1483 Get rights and content

Abstract

We have examined for a mutation in the cardiac β myosin heavy chain gene from Japanese patients with familial hypertrophic cardiomyopathy. A missense mutation due to a G to A transition in codon 935, leading to a replacement of Glu with Lys, was found in one patient. Family members of this patient were then examined. It was revealed that both the proband and his elder brother, who was also a symptomatic patient, were homozygous for the mutation. The proband eventually died of intractable heart failure, and his brother died suddenly in their thirties. On the other hand, his parents, who were first cousins and heterozygous for the mutation, had cardiac hypertrophy without clinical symptoms. His elder sister was also heterozygous for the mutation, however, she did not manifest with cardiac hypertrophy. These observations suggest a gene-dose-like effect of the mutant cardiac β myosin heavy chain gene on the clinical manifestation of familial hypertrophic cardiomyopathy.

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Cited by (58)

Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement
2012, Neuromuscular Disorders
Citation Excerpt :
Marked intrafamilial variation of the cardiac manifestations associated with certain MYH7 mutations has been documented, such as where the mother presented with proximal weakness in adulthood but her daughter manifested a cardiomyopathy from birth [32]. This clinical variability may relate to the presence of more than one MYH7 variation in cis, compound heterozygosity or homozygosity for two dominant MYH7 mutations [43–45]. Digeny for a second mutation concerning a functionally related protein [37,46] is another possibility and may explain the marked phenotypical variability observed in Family 1.
Central Core Disease (CCD) and Multi-minicore Disease (MmD) (the “core myopathies”) have been mainly associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the selenoprotein N (SEPN1) gene. A proportion of cases remain unresolved. Mutations in MYH7 encoding the beta myosin heavy chain protein have been implicated in cardiac and, less frequently, skeletal muscle disorders.
Here we report four patients from two families with a histopathological diagnosis of MmD, presenting in childhood with slowly progressive muscle weakness, more proximal in Family 1 and more distal in Family 2, and variable degrees of cardiorespiratory impairment evolving later in life. There was also a strong family history of sudden death in the first family. Muscle biopsies obtained in early childhood showed multiple minicores as the most prominent feature. Sequencing of the MYH7 gene revealed heterozygous missense mutations, c.4399C>G; p.Leu1467Val (exon 32) in Family 1 and c.4763G>C; p.Arg1588Pro (exon 34) in Family 2.
These findings suggest MYH7 mutations as another cause of a myopathy with multiple cores, in particular if associated with dominant inheritance and cardiac involvement. However, clinical features previously associated with this genetic background, namely a more distal distribution of weakness and an associated cardiomyopathy, may only evolve over time.
A homozygous MYBPC3 gene mutation associated with a severe phenotype and a high risk of sudden death in a family with hypertrophic cardiomyopathy
2009, Revista Espanola de Cardiologia
El estudio genético puede resultar una pieza clave en la evaluación integral de la miocardiopatía hipertrófica familiar y en el desarrollo de una medicina individualizada. Hay pocos casos descritos, pero existe un grupo de pacientes con genotipos complejos asociados a manifestación severa de la enfermedad y alto riesgo de muerte súbita. Presentamos una familia caracterizada por evolución precoz a disfunción sistólica y diastólica en algunos de sus integrantes y muerte súbita a edades tempranas en otros. Se detectó una mutación en homocigosis (IVS6+5G>A) en el gen de la proteína C de unión a la miosina, no descrita previamente, que nos permitió explicar el fenotipo de los afectados, estimar el riesgo en otros familiares y ofrecer consejo genético.
Genetic studies can play a key role in the comprehensive evaluation of familiar hypertrophic cardiomyopathy and in the development of individualized medicine. Although only a few cases have been described, there exists a group of patients with complex genotypes that are associated with severe disease manifestations and a high risk of sudden death. We describe a family in which some members experienced the early development of systolic and diastolic dysfunction while others experienced sudden death at a young age. We identified a novel homozygous mutation (IVS6+5G>A) in the myosin-binding protein-C gene that explained the phenotype of affected individuals and that enabled us to estimate the risk in other family members and to offer genetic counseling.
MYBPC3 gene variations in hypertrophic cardiomyopathy patients in India
2008, Canadian Journal of Cardiology
Hypertrophic cardiomyopathy (HCM) is a complex cardiac muscular disorder, inherited as an autosomal dominant disease with variable penetrance. Cardiac myosin-binding protein C (MyBPC) is the predominant myosin-binding protein isoform in the heart muscle. One hundred forty-seven mutations have been detected in MYBPC3, accounting for 15% of all HCM cases.
To screen exons 16, 18, 19, 22, 24, 28, 30, 31 and 34 in the MYBPC3 gene in Indian HCM patients.
Sixty control and 95 HCM samples were collected from cardiology units of the CARE Hospital (Nampally, Banjara Hills, Secunderabad, India) for genomic DNA isolation followed by polymerase chain reaction and single-stranded conformational polymorphism analysis.
Screening of the exons revealed two variations – one novel frame shift mutation in exon 19 at the nucleotide position 11577^11578 and one novel single nucleotide polymorphism (SNP) in codon 1093 of exon 31, coding for glycine with a C>T transition (GGC/GGT), in addition to the seven known SNPs mainly in the intronic region and one known missense mutation D770N in this population.
The novel frame shift mutation identified in exon 19, D570fs, with the insertion of an adenine residue in codon 570 coding for aspartate, results in a premature termination codon that produces a truncated protein lacking myosin- and titin-binding sites, explaining the role of the nonsense-mediated decay pathway. A novel SNP identified in codon 1093 of exon 31 was found to be a synonymous codon, which may have a regulatory effect at the translational level, attributing to affinity differences between codon-anticodon interactions. The screening of this gene may be relevant in the Indian context.
La myocardiopahie hypertrophique (MCH) est un trouble complexe du muscle cardiaque, hérité sous forme de maladie autosomique dominante à pénétration variable. La protéine C cardiaque de liaison à la myosine (MyBPC) est le principal isoforme de la protéine de liaison à la myosine du muscle cardiaque. On a décelé 147 mutations dans le gène MYBPC3 ce qui représente 15% de tous les cas de MCH.
Dépister les exons 16, 18, 19, 22, 24, 28, 30, 31 et 34 dans le gène MYBPC3 de patients indiens atteints de MCH.
Les auteurs ont colligé 60 sujets témoins et 95 échantillons de MCH dans des unités de cardiologie de l’Hôpital CARE (de Nampally dans les montagnes de Banjara à Secunderabad, en Inde) afin d’isoler l’ADN génomique et de procéder à une réaction en chaîne de la polymérase et à une analyse polymorphique conformationnelle monocaténaire.
Le dépistage des exons a révélé deux variations – une nouvelle mutation à trame décalée dans l’exon 19 à la position 11577^11578 du nucléotide et un nouveau polymorphisme d’un nucléotide simple (PNS) dans le codon 1093 de l’exon 31, qui code la glycine avec une transition C>T (GGC/GGT), en plus des sept PNS connus surtout situés dans la région intronique et d’une mutation faux-sens D770N connue au sein de notre population.
La nouvelle mutation à trame décalée repérée dans l’exon 19, D570fs, avec l’insertion d’un résidu d’adénine dans le codon 570 codant pour l’Asp {aspartate?}, provoque un codon de terminaison prématuré qui produit une protéine tronquée, sans liaison à la myosine et à la titine, ce qui explique le rôle de voie de désintégration à médiation de terminaison. Un nouveau PNS repéré dans le codon 1093 de l’exon 31 était un codon synonyme, qui pourrait avoir un effet régulateur au niveau traductionnel causé par les différences d’affinité entre interactions codonanticodon. Le dépistage de ce gène peut être pertinent en Inde.
Differences in diagnostic value of four electrocardiographic voltage criteria for hypertrophic cardiomyopathy in a genotyped population
2005, American Journal of Cardiology
Citation Excerpt :
Of the 97 genetically affected subjects, 30 were associated with the cardiac myosin-binding protein C gene mutation (Del593C, n = 4; Int21DSG+1A, n = 14; Arg820Gln, n = 12), 5 were associated with the β-myosin heavy chain gene mutation (Ala26Val, n = 3; Glu935Lys, n = 2), 21 were associated with the cardiac troponin T gene mutation (Arg92Trp, n = 8; Lys273Glu, n = 10; Val85Leu, n = 1; Phe110Ile, n = 2), and 41 were associated with the cardiac troponin I gene mutation (Lys183Del, n = 41). All mutations have been previously identified and described elsewhere.4,16–21 The demographics and clinical characteristics of the study population are listed in Table 1.
The diagnostic value of various classic electrocardiographic (ECG) voltage criteria for hypertrophic cardiomyopathy (HC) has not been established in a genotyped population. This study aimed to determine the most accurate diagnostic definition of classic ECG voltage criteria for detecting carriers of HC. ECG and echocardiographic findings were analyzed in 161 genotyped subjects (97 genetically affected, 64 unaffected) from 20 families with disease-causing mutations in 4 genes. The diagnostic value of 4 voltage criteria (Cornell, Sokolow-Lyon, Romhilt-Estes, and 12-lead QRS voltage) for detecting carriers of HC was investigated. In all subjects, the Romhilt-Estes (point score ≥4) criterion and 12-lead QRS voltage (≥240 mm) were most sensitive (37% and 36%, respectively), with high specificity (95% each), resulting in the greatest accuracy (60% and 59%, respectively). Using these criteria, in subjects without echocardiographic evidence of left ventricular hypertrophy, voltage abnormalities were found in 22.6% of carriers and 4.7% of noncarriers (p <0.01). In conclusion, these findings suggest that the Romhilt-Estes and the 12-lead QRS voltage criteria may be the most accurate diagnostic definitions for HC on the basis of molecular genetic diagnoses. Furthermore, this study demonstrated that voltage abnormalities may be found in prehypertrophic carriers. Even when genetic testing becomes widely available, it will be difficult to make genetic diagnoses in all patients with HC because of its genetic heterogeneity. Therefore, understanding the diagnostic value of classic ECG voltage criteria may be important in detecting carriers, including those without left ventricular hypertrophy.
Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties
2004, Journal of Molecular and Cellular Cardiology
Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and β-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P < 0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P < 0.05) and K_m for actin (+87%; P < 0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.
Stochastic allelic expression as trigger for contractile imbalance in hypertrophic cardiomyopathy
2020, Biophysical Reviews

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Regular ArticlePossible Gene Effect of a Mutant Cardiac β-Myosin Heavy Chain Gene on the Clinical Expression of Familial Hypertrophic Cardiomyopathy

Abstract

Regular Article
Possible Gene Effect of a Mutant Cardiac β-Myosin Heavy Chain Gene on the Clinical Expression of Familial Hypertrophic Cardiomyopathy