Counselling issues in familial hypertrophic cardiomyopathy.

Yu, Bing; French, J A; Jeremy, Richmond W.; French, Paul; McTaggart, D.; Nicholson, M. L.; Semsarian, C.; Richmond, David; Trent, Ronald J.

doi:10.1136/jmg.35.3.183

Cited by 22 publications

(17 citation statements)

References 21 publications

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“…Although only described in a small family, the R654H mutation was associated with low penetrance and only moderate hypertrophy even in adults, 24 whereas the N755K mutation was associated with near complete penetrance, quite marked hypertrophy even in children, and sudden cardiac death in 1 of 8 affected patients. 43 The site of interaction of C8 on the C5 domain remains speculative. The R654H and N755K mutations may result in a reduced affinity for C8 either because they are directly involved in the interaction or because they induce a conformational change that is transmitted to the binding interface.…”

Section: Circulation Research October 18 2002mentioning

confidence: 99%

Identification of Novel Interactions Between Domains of Myosin Binding Protein-C That Are Modulated by Hypertrophic Cardiomyopathy Missense Mutations

Moolman‐Smook

Flashman

Lange

et al. 2002

Circulation Research

155

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Abstract-Cardiac myosin binding protein-C (cMyBPC) is a modular protein consisting of 11 domains whose precise function and sarcomeric arrangement are incompletely understood. Identification of hypertrophic cardiomyopathy (HCM)-causing missense mutations in cMyBPC has highlighted the significance of certain domains. Of particular interest is domain C5, an immunoglobulin-like domain with a cardiac-specific insert, which is of unknown function yet is the site of two HCM-causing missense mutations. To identify interactors with this region, a human cardiac cDNA library was screened in a yeast two-hybrid (Y2H) assay using the C5 sequence as bait. Screening Ͼ7ϫ10 6 clones surprisingly revealed that domain C5 preferentially bound to clones encoding C-terminal fragments of cMyBPC; the interacting region was narrowed to domain C8 by deletion mapping. A surface plasmon resonance assay using purified recombinant cMyBPC domains was used to measure the affinity of C5 and C8 in vitro (K a ϭ1ϫ10 5 mol/L Ϫ1 ). This affinity was decreased about 2-fold by the HCM mutation R654H, and by at least 10-fold by the mutation N755K. Further Y2H assays also demonstrated specific binding between domains C7 and C10 of cMyBPC. Based on these novel interactions, and previous biochemical and structural data, we propose that cMyBPC molecules trimerize into a collar around the thick filament, with overlaps of domains C5-C7 of one cMyBPC with C8-C10 of another. We speculate that this interaction may be dynamically formed and released, thereby restricting or favoring cross-bridge formation, respectively. We suggest that the HCM mutations act by altering the cMyBPC collar, indicating its importance in thick filament structure and regulation.

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Section: Circulation Research October 18 2002mentioning

confidence: 99%

Identification of Novel Interactions Between Domains of Myosin Binding Protein-C That Are Modulated by Hypertrophic Cardiomyopathy Missense Mutations

Moolman‐Smook

Flashman

Lange

et al. 2002

Circulation Research

155

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“…It has been argued that those living with a familial risk of HCM, but without symptoms, may face so much uncertainty that even a positive DNA test has the potential to restore a sense of control or provide reassurance (Christiaans et al 2009a), as has been recorded in relation to DNA tests for other disorders (Marteau and Mitchie 1995). Another area of significant concern for those at risk of inherited cardiac conditions are issues relating to children (and grandchildren) and reproduction (Anderson et al 2008;Charron et al 2002;Farnsworth et al 2006;Hendriks et al 2005;van Langen et al 2004, Yu et al 1997. It has been shown with respect to HCM, however, that worry can be alleviated by attending specialized cardiac genetics clinics (Ingles et al 2008), and this has also been recommended for those at risk of LQTs (Anderson et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…This knowledge can then also be used to screen relatives with a greater degree of certainty than clinical examinations alone (Yu et al 1997), allowing for the discharge of those without a mutation (people who would otherwise have been treated as at risk) and the identification of clinically unaffected but genetically at risk individuals (with the potential for preventing sudden cardiac death). However, as the genes involved in these disorders have variable expressivity and penetrance (Vincent 1998;Yu et al 1997) being diagnosed as "genetically at risk" does not necessarily provide insights into variability in phenotype and symptoms (Farnsworth et al 2006). Also, the "predict and prevent" strategy relies on information about the disorder and the possible inventions being communicated within families -a responsibility which usually falls to the proband.…”

Section: Introductionmentioning

confidence: 99%

Impediments to DNA Testing and Cascade Screening for Hypertrophic Cardiomyopathy and Long QT syndrome: A Qualitative Study of Patient Experiences

Smart

2010

Journal of Genetic Counseling

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Background/AimsThis paper reports data from a qualitative study of patient experiences of DNA testing and cascade screening for hypertrophic cardiomyopathy and long QT syndrome, cardiac conditions that place sufferers at risk of sudden death. The paper particularly focuses on potential impediments to testing and screening. Methods Semi-structured interviews were undertaken with a purposive sample of 27 people in the UK who had undergone testing. ResultsIn the context of the uncertainties that can characterize experiences of these disorders, the majority of participants in this sample embraced testing and screening as a way of providing health information for themselves or their relatives (particularly children). There was nevertheless evidence of ambivalence about the value and impact of the DNA test information which could influence participants' dispositions toward testing, and play into dilemmas about family communication. Other concerns arose in relation to communicating about these disorders, decisions to involve elderly relatives and pressures relating to family responsibility. ConclusionThe evidence of ambivalence provides insight into why some people may be resistant to testing, screening and sharing information. The findings about communication processes indicate potential areas of concern for the cascading process.

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“…The protein belongs to the immunoglobulin superfamily and its three isoforms show a highly conserved structure consisting of IgI and fibronectin domains (12). A large number (currently Ͼ 19) of mutations in cardiac MyBP-C has been linked to FHC, with most resulting in reading frame shifts and premature termination as a result of the generation of a nonsense codon (3,(13)(14)(15)(16). The truncations most frequently include the titin and/or the myosin binding regions that are located in the COOH-terminal one-third of the molecule.…”

Section: Introductionmentioning

confidence: 99%

A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.

et al. 1998

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Familial hypertrophic cardiomyopathy can be caused by mutations in genes encoding sarcomeric proteins, including the cardiac isoform of myosin binding protein C (MyBP-C), and multiple mutations which cause truncated forms of the protein to be made are linked to the disease. We have created transgenic mice in which varying amounts of a mutated MyBP-C, lacking the myosin and titin binding domains, are expressed in the heart. The transgenically encoded, truncated protein is stable but is not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the pCa 2 ϩ -force curve and, importantly, their power output was reduced. Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, resulting in a striking pattern of sarcomere disorganization and dysgenesis. ( J. Clin. Invest.

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Counselling issues in familial hypertrophic cardiomyopathy.

Cited by 22 publications

References 21 publications

Identification of Novel Interactions Between Domains of Myosin Binding Protein-C That Are Modulated by Hypertrophic Cardiomyopathy Missense Mutations

Identification of Novel Interactions Between Domains of Myosin Binding Protein-C That Are Modulated by Hypertrophic Cardiomyopathy Missense Mutations

Impediments to DNA Testing and Cascade Screening for Hypertrophic Cardiomyopathy and Long QT syndrome: A Qualitative Study of Patient Experiences

A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.

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