Early Results of Sarcomeric Gene Screening from the Egyptian National BA-HCM Program

Kassem, Heba Sh.; Azer, Remon S.; Saber-Ayad, Maha; Moharem-Elgamal, Sarah; Magdy, Gehan; ElGuindy, Ahmed; Cecchi, Fabiola; Olivotto, Iacopo; Yacoub, Magdi H.

doi:10.1007/s12265-012-9425-0

Cited by 33 publications

(28 citation statements)

References 44 publications

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“…Since two relatively recent reviews list known mutations until 2013 (223, 274), Table 9 includes additional mutations that were not included or identified since then, while Figure 10 indicates the total number of currently known mutations per domain.…”

Section: Myosin Binding Protein-cmentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

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Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.

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Section: Myosin Binding Protein-cmentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

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“…Genetic causes can typically be found in 50 to 75 % of cases of hypertrophic cardiomyopathy; expanding the genetic screening analysis through increasing application of NGS technology to enable simultaneous investigation of a broad panel of inherited genes is projected to augment the genetic-positive yield [97]. In those patients in whom a mutation is identified, about 80 % involve two genes (encoding myosin heavy chain 7 and myosin-binding protein C—see Table 1).…”

Section: Hcm: Morphomechanical Phenotypic Characteristicsmentioning

confidence: 99%

Linking Genes to Cardiovascular Diseases: Gene Action and Gene–Environment Interactions

Pasipoularides

2015

J. of Cardiovasc. Trans. Res.

121

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A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the “post-genomic” era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how “modifier genes” influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many—practitioners and investigators—to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area.

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“…Here, we studied three disease causing missense mutations of the domain C1 that were recently identified in Egypt for the first time by Kassem et al, [12]. These HCM causing mutations: (i) Arg177His (ii) Ala216Thr and (iii) Glu258Lys are located in the strand-B, the D/E loop and the C-terminal of strand-G, respectively (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…A mutational analysis study on an Egyptian cohort through Bibliotheca Alexandrina HCM (BA-HCM), a national programme showed that mutations in cardiac MyBP-C (cMyBP-C) gene are a common cause of HCM in Egypt [12]. More than 200 disease causing mutations have been reported in the cMyBP-C [7], [13]–[19].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, Glu258Lys has been reported to cause a founder effect in Italian population [38]. Clinical studies suggest the effect of mutations (ie., contractile dysfunction [7], [8], [12], [15], [18], [36]–[38]), yet less is known about their structure-function relationship. Although the structural positions of the mutations are known [26]–[28], their exact role in causing HCM is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C

et al. 2013

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Cardiac myosin binding protein-C (cMyBP-C) is a multi-domain (C0–C10) protein that regulates heart muscle contraction through interaction with myosin, actin and other sarcomeric proteins. Several mutations of this protein cause familial hypertrophic cardiomyopathy (HCM). Domain C1 of cMyBP-C plays a central role in protein interactions with actin and myosin. Here, we studied structure-function relationship of three disease causing mutations, Arg177His, Ala216Thr and Glu258Lys of the domain C1 using computational biology techniques with its available X-ray crystal structure. The results suggest that each mutation could affect structural properties of the domain C1, and hence it’s structural integrity through modifying intra-molecular arrangements in a distinct mode. The mutations also change surface charge distributions, which could impact the binding of C1 with other sarcomeric proteins thereby affecting contractile function. These structural consequences of the C1 mutants could be valuable to understand the molecular mechanisms for the disease.

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Early Results of Sarcomeric Gene Screening from the Egyptian National BA-HCM Program

Cited by 33 publications

References 44 publications

Thick Filament Protein Network, Functions, and Disease Association

Thick Filament Protein Network, Functions, and Disease Association

Linking Genes to Cardiovascular Diseases: Gene Action and Gene–Environment Interactions

Molecular Modeling of Disease Causing Mutations in Domain C1 of cMyBP-C

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