Novel mutations in MYH7 and MYBPC3 of an Indian family causing hypertrophic cardiomyopathy

Sakthievel, Sadayappan; Waldmüller, Stephan; Saadi, Abdelkrim; Joseph, Pulavelil Kurian; Rakesh, P.G.; Padmakumar, R; Jagan, M Tharakan; Richard, Pascale; Schwartz, Ketty; Rajamanickam, C.; Vosberg, Hans−Peter

doi:10.1016/s0022-2828(01)90416-x

Cited by 6 publications

(7 citation statements)

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“…This MYBPC3 ΔInt32 variant has been previously established to cause various cardiomyopathies, including hypertrophic, dilated, and restrictive and coronary artery disease [20,21] in a sizeable percentage of South Asians [23]. Its presence was also found to be associated with development of left ventricular dysfunction in South Asian patients with coronary artery disease [20].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we discovered a 25-basepair (bp) deletion in the MYBPC3 gene, identified as MYBPC3 ΔInt32 , to be particularly prevalent among individuals of South Asian ancestry [15,16]. This variant is the focus of the current study and is characterized by the loss of the splicing branch point in intron 32, leading to the skipping of exon 33 and a frameshift starting in exon 34, This results in the replacement of 62 amino acids with a novel 55 amino acid sequence in the C10 domain of the C-terminus of cMyBP-C.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, heterozygous MYBPC3 ΔInt32 variant carriers have highly variable disease onset and typically develop symptoms of HCM during the third decade of life. Strikingly, an additive effect of MYBPC3 mutations with other sarcomeric protein mutations, a so-called “two-hit phenomenon,” results in severe cardiac hypertrophy, early sudden cardiac death [17–19] and coronary artery disease [20,21]. For example, if carriers of the MYBPC3 ΔInt32 variant also carry a mutation in β -myosin heavy chain, this combination frequently results in sudden cardiac death [22].…”

Section: Introductionmentioning

confidence: 99%

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High-Throughput Diagnostic Assay for a Highly Prevalent Cardiomyopathy-Associated MYBPC3 Variant

Barefield

Lynch

Jagadeesan

et al. 2016

J Mol Biomark Diagn

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A 25-basepair deletion variant of MYBPC3 occurs at high frequency in individuals of South Asian descent and is estimated to affect 55 million people worldwide, carrying an increased likelihood of cardiomyopathy. Since this variant is prevalent and severe in this subpopulation, quick and affordable screening to provide risk-assessment to guide treatment for these patients is critical. An RNaseH qPCR assay was developed to quickly and specifically diagnose the presence of the 25-basepair deletion variant in MYBPC3. RNAseH-blocked nucleotide primers were designed to identify the presence or absence of the wild type MYBPC3 allele or the genomic sequence containing the 25-basepair deletion. Using this assay, three blinded operators were able to accurately determine the genotype from human genomic DNA samples from blood and saliva using a qPCR thermocycler. Furthermore, positive variant subjects were examined by both electrocardiography and echocardiography for the presence of cardiomyopathy. A simple, robust assay was established, verified and validated that can be automated to detect the presence of the highly prevalent 25-basepair deletion MYBPC3 variant using both blood and saliva samples. The assay will provide quick and accurate prescreening of individuals at high risk for cardiomyopathies and allow for better clinical identification of 25-basepair deletion MYBPC3 carriers in large cohort epidemiological studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High-Throughput Diagnostic Assay for a Highly Prevalent Cardiomyopathy-Associated MYBPC3 Variant

Barefield

Lynch

Jagadeesan

et al. 2016

J Mol Biomark Diagn

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“…The genotype-phenotype correlations of MyBPC are very diverse due to the multiplicity of genes and environmental factors influencing the clinical outcome. For example, the occurrence of a MYH7 mutation in MYBPC3 Δ25bp carriers frequently leads to sudden cardiac death [43]. Extensive genetic screening approaches can discover additional risk factors for genetic variants with an incomplete penetrance for the development of HCM, has been demonstrated for the MYBPC3 Δ25bp/D389V variant [48].…”

Section: Discussionmentioning

confidence: 99%

“…The common MYBPC3 Δ25bp variant with a 25 base pair intron deletion in intron 32 has been associated with an increased odds ratio of 6.99 for the development of HCM, affecting an estimated 100 million carriers in the South Asian population [43][44][45]. These studies showed that transcripts originating from the affected allele are subject to alternative splicing mechanisms that lead to skipping of exon 33.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin–Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy–causing Double Mutation MYBPC3Δ25bp/D389V

Schwäbe¹,

Peter²,

Taft³

et al. 2021

Preprint

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Cardiac myosin-binding protein C (MyBPC) is a thick-filament associated regulatory protein in the sarcomere. It regulates the sensitive contractile system of the myocardium by acting as a mechanical tether, sensitizing the thin filament or modulating myosin motor activity. Mutations in the MYBPC3 gene are a frequent cause for the development of hypertrophic cardiomyopathy, the most frequent cardiac disorder. Recently, the monoallelic double mutation MYBPC3Δ25bp/D389V has been discovered as a subset of the common MYBPC3Δ25bp variant in South Asia. MYBPC3Δ25bp/D389V carriers exhibit hyperdynamic features, which are considered an early finding for the development of hypertrophic cardiomyopathy. Using correlation-guided molecular dynamics simulations sampling, we show that the D389V mutation shifts the conformational distribution of the C2 domain of MyBPC. We further applied biochemical approaches to probe the effects of the D389V mutation on structure, thermostability and protein-protein interactions of MyBPC C2. The melting temperature (Tm) of MyBPC C2 D389V is decreased by 4 to 7 °C compared to wild type while the interaction of the C0-C2 domains with myosin and actin remains unchanged. Additionally, we utilized steered molecular dynamics (SMD) simulations to investigate the altered unfolding pathway of MyBPC C2 D389V. Based on our data, we propose a pathomechanism for the development of HCM in MYBPC3Δ25bp and MYBPC3Δ25bp/D389V carriers.

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Genetic, clinical, molecular, and pathogenic aspects of the South Asian–specific polymorphic MYBPC3Δ25bp variant

et al. 2020

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Novel mutations in MYH7 and MYBPC3 of an Indian family causing hypertrophic cardiomyopathy

Cited by 6 publications

References 0 publications

High-Throughput Diagnostic Assay for a Highly Prevalent Cardiomyopathy-Associated MYBPC3 Variant

High-Throughput Diagnostic Assay for a Highly Prevalent Cardiomyopathy-Associated MYBPC3 Variant

Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin–Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy–causing Double Mutation MYBPC3Δ25bp/D389V

Genetic, clinical, molecular, and pathogenic aspects of the South Asian–specific polymorphic MYBPC3Δ25bp variant

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