Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice

McConnell, Bradley K.; Jones, Karen A.; Fatkin, Diane; Arroyo, Luis H.; Lee, R. T.; Aristizábal, Orlando; Turnbull, Daniel H.; Georgakopoulos, Dimitrios; Kass, David A.; Bond, Meredith; Niimura, Hideshi; Schöen, Frederick J.; Conner, David A.; Fischman, Donald A.; Seidman, C E; Seidman, Jonathan G.

doi:10.1172/jci7377c1

Cited by 89 publications

(124 citation statements)

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“…The results also showed that the mutant protein behaved as a poison polypeptide (Yang et al 1999). The mouse model of a homozygous mutant MyBPC3 gene was shown to result in dilated cardiomyopathy (McConnell et al 1999). A knock-in mouse model of the N-terminal deleted gene was created recently (Witt et al 2001).…”

Section: Characterization Of Specific Myh7 Mutationsmentioning

confidence: 99%

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Bashyam¹,

Savithri

Kumar³

et al. 2003

J Hum Genet

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Section: Characterization Of Specific Myh7 Mutationsmentioning

confidence: 99%

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Bashyam¹,

Savithri

Kumar³

et al. 2003

J Hum Genet

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“…In both myosin heavy chain and myo- sin-binding protein C mouse models, homozygosity leads to a dilated cardiomyopathy (DCM), i.e. dilatation of heart chambers with reduced contractile function [67], [68]. In the Arg403Gln homozygote mice, DCM occurs in neonates and all mice die of heart failure by age 7 days [67].…”

Section: Animal Modelsmentioning

confidence: 99%

“…In the Arg403Gln homozygote mice, DCM occurs in neonates and all mice die of heart failure by age 7 days [67]. In contrast, homozygous myosin-buding protein c mice develop DCM by age 3 weeks, but subsequently develop compensatory hypertrophy and indeed have a normal lifespan [68]. The ability of being able to breed these mice to both heterozygosity and homozygosity has resulted in clinically relevant models of human HCM and DCM and provide a platform for further studies to both understand pathogenesis, and to potentially identify therapeutic options and targets.…”

Section: Animal Modelsmentioning

confidence: 99%

“…In addition, recent studies in a myosin-binding protein C mouse model of HCM show that while these mice may exhibit very mild disease based on cardiac function studies and histopathology analysis, electrophysiological testing suggests that there is a significantly increased vulnerability to ventricular arrhythmias, and therefore sudden death [70]. M-mode and two-dimensional echocardiography in mice has also enabled accurate assessment of left ventricular hypertrophy, changes in cardiac dimensions, and systolic function (fractional shortening) [62,[66][67][68]. More recently application of magnetic resonance imaging (MRI) has enabled detailed assessment of heart structure and even congenital malformations (e.g.…”

Section: Animal Modelsmentioning

confidence: 99%

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Hypertrophic cardiomyopathy: from gene defect to clinical disease

2003

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Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for treating cardiovascular disease in man.

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“…21 Thirdly, strong expression of Opn has been demonstrated in macrophages in necrotic lesions of human myocardial infarction and after myocardial freeze-thaw injury in rats. 22 Dystrophic calcification of necrotic myocardium has been observed in some gene-targeted mouse models of cardiomyopathy [23][24][25] : in mice with inactivation of desmin, the authors reported strong Opn expression in co-localization with calcified myocardial necrosis, yet function and regulation of Opn were not elucidated further. 25 Cer-tain predisposed inbred mouse strains, including DBA/2, BALB/c, and C3H/He, also develop dystrophic peri-/myocardial calcification spontaneously or in response to high-fat/low-protein diets, 26,27 viral myocarditis, 28 or direct freeze-thaw injury.…”

mentioning

confidence: 99%

A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice

Aherrahrou

Axtner

Kaczmarek

et al. 2004

The American Journal of Pathology

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Calcification of necrotic tissue is frequently observed in chronic inflammation and atherosclerosis. A similar response of myocardium to injury, referred to as dystrophic cardiac calcinosis (DCC), occurs in certain inbred strains of mice. We now examined a putative inhibitor of calcification, osteopontin, in DCC after transdiaphragmal myocardial freeze-thaw injury. Strong osteopontin expression was found co-localizing with calcification in DCC-susceptible strain C3H/ HeNCrlBr, which exhibited low osteopontin plasma concentrations otherwise. Osteopontin mRNA induction was 20-fold higher than in resistant strain C57BL/ 6NCrlBr, which exhibited fibrous lesions without calcification and little osteopontin expression. Sequence analysis identified several polymorphisms in calcium-binding and phosphorylation sites in osteopontin cDNA. Their potential relevance for DCC was tested in congenic mice, which shared the osteopontin locus with C57BL/6NCrlBr, but retained a chromosomal segment from C3H/HeNCrlBr on proximal chromosome 7. These mice exhibited strong osteopontin expression and DCC comparable to C3H/HeNCrlBr suggesting that a trans-activator of osteopontin transcription residing on chromosome 7 and not the osteopontin gene on chromosome 5 was responsible for the genetic differences in osteopontin expression. A known osteopontin activator encoded by a gene on chromosome 7 is the transforming growth factor-␤1, which was more induced (3.5؋) in C3H/HeNCrlBr than in C57BL/6NCrlBr mice.

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Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice

Cited by 89 publications

References 0 publications

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

Hypertrophic cardiomyopathy: from gene defect to clinical disease

A Locus on Chromosome 7 Determines Dramatic Up-Regulation of Osteopontin in Dystrophic Cardiac Calcification in Mice

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