scholarly journals A Zebrafish Model of a Human Titin-truncating Mutation Exhibits Spontaneous, Age-dependent and Load-exacerbated Dilated Cardiomyopathy

2017 ◽  
Vol 26 ◽  
pp. S43
Author(s):  
I. Huttner ◽  
L. Wang ◽  
C. Santiago ◽  
C. Horvat ◽  
R. Johnson ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Zebrafish Model ◽  
Truncating Mutation ◽  
Age Dependent

Abstract 194: Characterization of Arrhythmogenic Dilated Cardiomyopathy Caused by Novel Filamin C Splice Variant in a Zebrafish Model

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Rene L Begay ◽  
Teisha J Rowland ◽  
Charles A Tharp ◽  
August Martin ◽  
Sharon L Graw ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Splice Variant ◽  
Systolic Dysfunction ◽  
Family Members ◽  
Muscle Disease ◽  
Heart Tube ◽  
Zebrafish Model ◽  
Cell Stage ◽  
Cardiac Phenotype ◽  
Filamin C

Although dilated cardiomyopathy (DCM) is a serious and frequent genetic cause of heart failure, only 30-40% of cases can be attributed to a known DCM gene mutation. To identify and confirm additional disease genes involved in DCM, we performed whole exome sequencing in two multigenerational families with DCM, both from the same geographic region of Italy, and found a novel splice variant in the gene encoding filamin-C (FLNC). Previously characterized mutations in FLNC had been primarily linked to skeletal muscle disease, although none of the affected family members displayed skeletal myopathy. To confirm and further characterize the arrhythmogenic DCM phenotype observed in family members, we performed embryonic knockdown experiments using morpholino (MO) treatment in zebrafish (Danio rerio) targeting the FLNC ortholog, filamin Cb (flncb). Following MO injection into 1-2 cell stage zebrafish embryos, 63.4% (78 of 123) of viable flncb MO-injected embryos displayed a cardiac phenotype at 72 hours post fertilization (hpf) (vs. 17.0% [30 of 177] of control MO-injected embryos; p≤0.001). Increases in mortality were observed, with 20.8% (54 of 260) of flncb MO-injected embryos surviving at 7 days post fertilization (vs. 65% [162 of 249] of control embryos; p≤0.001). The flncb MO-injected embryos demonstrated pericardial edema, dysmorphic or dilated cardiac chambers, and abnormal looping of the heart tube suggestive of systolic dysfunction. The flncb MO-injected embryos additionally demonstrated a lower mean stroke volume than controls (0.076 vs. 0.181 nl; p=0.015), a reduced mean cardiac output (10.8 vs. 25 nl/min; p=0.02), and an increase in the fraction of retrograde blood flow over the cardiac cycle (0.42 vs. 0.03; p=0.027). Overall, this flncb MO treatment recapitulated a DCM phenotype similar to the state caused by the human splicing variant, supporting haploinsufficiency as the mechanism leading to DCM in these families. Our findings suggest that approaches to augment endogenous filamin C protein levels may represent a viable treatment strategy that warrants exploration in future studies.

scholarly journals Cardiac-Specific Cre Induces Age-Dependent Dilated Cardiomyopathy (DCM) in Mice

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1189 ◽  
Author(s):  
Taha Rehmani ◽  
Maysoon Salih ◽  
Balwant Tuana
Keyword(s):  
Dna Damage ◽  
Dilated Cardiomyopathy ◽  
Protein Function ◽  
Mouse Genome ◽  
Model System ◽  
Dependent Manner ◽  
Cardiac Pathology ◽  
Damage Response ◽  
Age Dependent ◽  
Invaluable Tool

The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre recombinase can cause DNA damage, the consequences of which can be very detrimental to mouse health. Previously published literature on the most utilized cardiac-specific cre, αMHC-cre, mouse model exhibited a nonlethal hypertrophic cardiomyopathy (HCM) with aging. However, using the same αMHC-cre mice, we observed a cardiac pathology, resulting in complete lethality by 11 months of age. Echocardiography and histology revealed that the αMHC-cre mice were displaying symptoms of dilated cardiomyopathy (DCM) by seven months of age, which ultimately led to their demise in the absence of any HCM at any age. Molecular analysis showed that this phenotype was associated with the DNA damage response through the downregulation of activated p38 and increased expression of JNK, p53, and Bax, known inducers of myocyte death resulting in fibrosis. Our data urges strong caution when interpreting the phenotypic impact of gene responses using αMHC-cre mice, since a lethal DCM was induced by the cre driver in an age-dependent manner in this commonly utilized model system.

scholarly journals Prevalence and clinical importance of titin truncating variants in adults without known congestive heart failure

2019 ◽  
Author(s):  
James P. Pirruccello ◽  
Alexander Bick ◽  
Samuel Friedman ◽  
Mark Chaffin ◽  
Krishna G. Aragam ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Clinical Importance ◽  
Middle Aged ◽  
Cross Sectional ◽  
Truncating Mutation ◽  
Cross Sectional Studies

AbstractBackgroundCross-sectional studies of various forms of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin (‘TTNtv’) in 7-30% of patients, but the clinical importance of identifying a TTNtv in an asymptomatic adult is largely unknown. In contrast to cross-sectional studies, prospective cohort studies allow for unbiased estimates of the disease risks associated with a genotype exposure.ObjectivesTo determine the prevalence of cardiac imaging abnormalities and risk of incident disease among middle-aged TTNtv carriers without known congestive heart failure.MethodsWe analyze exome sequencing data of 45,747 participants of the UK Biobank without known congestive heart failure to identify TTNtv carriers. Among 10,552 with cardiac magnetic resonance imaging (MRI), we determine the relationship between TTNtv carrier status and left ventricular ejection fraction. In this prospective cohort, we quantify the absolute and relative risks of incident disease in TTNtv carriers versus noncarriers.ResultsAmong 45,747 middle-aged participants without known congestive heart failure, 196 (0.43%) harbored a TTNtv. The average ejection fraction was 61% in TTNtv carriers versus 65% in noncarriers (P = 1.8 × 10−8), with a 9.3-fold increase (95% CI 3.9 – 22.2) in odds of subnormal ejection fraction (P = 5.7 × 10−5). Over a median follow-up of 6.9 years, a composite endpoint of incident dilated cardiomyopathy, congestive heart failure, or all-cause mortality was observed in 6.6% of TTNtv carriers versus 2.9% of non-carriers (adjusted hazard ratio 2.5; 95% CI 1.4 – 4.3; p = 1.1 × 10−3).ConclusionsApproximately 1 in 230 middle-aged adults without known congestive heart failure harbored a TTNtv. These carriers had a substantially increased relative risk—but modest absolute risk—of having a subnormal ejection fraction or manifesting clinical disease during prospective follow-up.Condensed AbstractCross-sectional studies of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin (‘TTNtv’) in up to 30% of patients—but the clinical importance of TTNtv in asymptomatic adults is largely unknown. Here, we observe a TTNtv in 0.43% of 45,747 middle-aged adults. Average ejection fraction was 61% in TTNtv carriers versus 65% in non-carriers (p<0.001). Over a median follow-up of 7 years, incident congestive heart failure or mortality was observed in 6.6% of TTTtv carriers versus 2.9% of non-carriers (hazard ratio 2.5; p = 0.001).

scholarly journals CFTR deficiency causes cardiac dysplasia during zebrafish embryogenesis and is associated with dilated cardiomyopathy

2020 ◽  
Author(s):  
Yanyan Liu ◽  
Ziyuan Lin ◽  
Mingfeng Liu ◽  
Huijuan Liao ◽  
Yan Chen ◽  
...  
Keyword(s):  
Heart Disease ◽  
Dilated Cardiomyopathy ◽  
Heart Development ◽  
Cardiac Development ◽  
Myocardial Dysfunction ◽  
Primary Defect ◽  
Zebrafish Model ◽  
Human Heart Failure ◽  
Stage Of Development

Abstract Background: Mutations in the CFTR gene cause cystic fibrosis (CF) with myocardial dysfunction. However, it remains unknown whether CF-related heart disease is a secondary effect of pulmonary disease, or an intrinsic primary defect in the CF heart. Results: Here, we used a zebrafish model, which lacks lung tissue, to investigate the role of CFTR in cardiogenesis during embryonic development. Our findings demonstrate that a loss of CFTR impairs cardiac development from the cardiac progenitor stage of heart development, resulting in cardiac looping defects, a dilated atrium, pericardial edema, and a decrease in heart rate. Furthermore, we found that cardiac development is perturbed in wild type embryos treated with a gating specific Cftr channel inhibitor, CFTRinh-172, at the blastula stage of development, but not with treatment at later stages. Gene expression analysis of blastulas indicated that transcript levels, including mRNAs associated with cardiovascular diseases, were significantly altered in embryos derived from cftr mutants relative to controls. To evaluate the role of CFTR in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found that CFTR containing I556V mutation, which causes a channel defect, is associated with the disease. Similar to well-studied channel-defective CFTR mutants, CFTR I556V mRNA failed to restore cardiac dysplasia in mutant embryos. Conclusions: The present study reveals an important role for the CFTR ion channel in regulating cardiac development during early embryogenesis, supporting the hypothesis that CF-related heart disease results from an intrinsic primary defect in the CF heart.

Could the Changes of Active Myocarditis in Patients With Dilated Cardiomyopathy Be Time- and Age-Dependent?

2021 ◽  
Vol 161 ◽  
pp. 122-123
Author(s):  
Rajeev Gupta ◽  
Fady Gerges ◽  
Galal Eldin Nagib Elkilany ◽  
Neelesh Gupta
Keyword(s):  
Dilated Cardiomyopathy ◽  
Age Dependent

scholarly journals Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Grażyna T. Truszkowska ◽  
Zofia T. Bilińska ◽  
Angelika Muchowicz ◽  
Agnieszka Pollak ◽  
Anna Biernacka ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Truncating Mutation ◽  
Whole Exome

scholarly journals Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

2021 ◽  
Vol 8 (2) ◽  
pp. 10
Author(s):  
Celine F. Santiago ◽  
Inken G. Huttner ◽  
Diane Fatkin
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Genetic Disorders ◽  
Zebrafish Model ◽  
Sarcomeric Protein ◽  
Treatment And Prevention ◽  
Muscle Disorder ◽  
Genetic And Environmental Factors ◽  
Sarcomere Assembly

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.

scholarly journals CFTR deficiency causes cardiac dysplasia during zebrafish embryogenesis and is associated with dilated cardiomyopathy

2019 ◽  
Author(s):  
Yanyan Liu ◽  
Ziyuan Lin ◽  
Mingfeng Liu ◽  
Huijuan Liao ◽  
Yan Chen ◽  
...  
Keyword(s):  
Heart Disease ◽  
Dilated Cardiomyopathy ◽  
Heart Development ◽  
Cardiac Development ◽  
Myocardial Dysfunction ◽  
Primary Defect ◽  
Zebrafish Model ◽  
Human Heart Failure ◽  
Stage Of Development

Abstract Mutations in the CFTR gene cause cystic fibrosis with myocardial dysfunction. However, it remains unknown whether CF-related heart disease is a secondary effect of pulmonary disease, or an intrinsic primary defect in the CF heart. Here, we used a zebrafish model, which lacks lung tissue, to investigate the role of CFTR in cardiogenesis during embryonic development. Our findings demonstrate that a loss of CFTR impairs cardiac development from the cardiac progenitor stage of heart development, resulting in cardiac looping defects, a dilated atrium, pericardial edema, and a decrease in heart rate. Furthermore, we found that cardiac development is perturbed in wild type embryos treated with a gating specific Cftr channel inhibitor, CFTRinh-172, at the blastula stage of development, but not with treatment at later stages. Gene expression analysis of blastulas indicated that transcript levels, including mRNAs associated with cardiovascular diseases, were significantly altered in embryos derived from cftr mutants relative to controls. To evaluate the role of CFTR in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found that CFTR containing I556V mutation, which causes a channel defect, is associated with the disease. Similar to well-studied channel-defective CFTR mutants, CFTR I556V mRNA failed to restore cardiac dysplasia in mutant embryos.The present study reveals an important role for the CFTR ion channel in regulating cardiac development during early embryogenesis, supporting the hypothesis that CF-related heart disease results from an intrinsic primary defect in the CF heart.

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