scholarly journals Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24

2019 ◽  
Vol 28 (11) ◽  
pp. 1919-1929 ◽  
Author(s):  
Carola Hedberg-Oldfors ◽  
Alexandra Abramsson ◽  
Daniel P S Osborn ◽  
Olof Danielsson ◽  
Afsoon Fazlinezhad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Heart Defects ◽  
Cardiovascular Disorder ◽  
Cardiac Transplant ◽  
Genome Wide ◽  
Homozygous Mutations ◽  
Additional Support ◽  
And Function ◽  
Muscle Biopsies

Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.

scholarly journals A rare missense mutation inMYH6confers high risk of coarctation of the aorta

2017 ◽  
Author(s):  
Thorsteinn Bjornsson ◽  
Rosa B. Thorolfsdottir ◽  
Gardar Sveinbjornsson ◽  
Patrick Sulem ◽  
Gudmundur L. Norddahl ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Heart Defects ◽  
Coarctation Of The Aorta ◽  
Population Level ◽  
Genome Wide ◽  
Cardiac Syndrome ◽  
A Genome ◽  
And Function

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment1. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp inMYH6(odds ratio (OR) = 44.2,P= 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF)2. These findings suggest that p.Arg721Trp inMYH6causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development and function.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

scholarly journals The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation

2012 ◽  
Vol 302 (11) ◽  
pp. H2139-H2147 ◽  
Author(s):  
Brian Wadugu ◽  
Bernhard Kühn
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Critical Role ◽  
Special Focus ◽  
Cardiomyocyte Proliferation ◽  
Neuregulin 1 ◽  
Adult Heart ◽  
Signaling Complex ◽  
And Function

The signaling complex consisting of the growth factor neuregulin-1 (NRG1) and its tyrosine kinase receptors ErbB2 and ErbB4 has a critical role in cardiac development and homeostasis of the structure and function of the adult heart. Recent research results suggest that targeting this signaling complex may provide a viable strategy for treating heart failure. Clinical trials are currently evaluating the effectiveness and safety of intravenous administration of recombinant NRG1 formulations in heart failure patients. Endogenous as well as administered NRG1 has multiple possible activities in the adult heart, but how these are related is unknown. It has recently been demonstrated that NRG1 administration can stimulate proliferation of cardiomyocytes, which may contribute to repair failing hearts. This review summarizes the current knowledge of how NRG1 and its receptors control cardiac physiology and biology, with special emphasis on its role in cardiomyocyte proliferation during myocardial growth and regeneration.

scholarly journals Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Shah ◽  
◽  
Albert Henry ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Cardiac Development ◽  
Association Studies ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors

2005 ◽  
Vol 93 (02) ◽  
pp. 212-219 ◽  
Author(s):  
Zamaneh Kassiri ◽  
Rama Khokha
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Critical Role ◽  
Left Ventricular ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western World ◽  
A Disintegrin And Metalloproteinase ◽  
And Function ◽  
Myocardial Injuries

SummaryCardiovascular disease poses a major health care burden in the Western world. Following myocardial injuries, ventricular remodelling and dysfunction ensue, which can eventually culminate in heart failure. An important event in left ventricular (LV) remodelling is alteration of the extracellular matrix (ECM) integrity, the structural network that interconnects the myocardial components. The critical role of ECM remodelling in cardiac dilation and heart failure was recognized more than a decade ago, and the molecular factors responsible for this process are now being explored. Abnormal ECM turnover is primarily brought about by an imbalance in the activity of matrix metalloproteinases (MMPs) that degrade ECM components, and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Here we provide an overview of composition of the cardiac ECM, and alterations in ECM regulatory proteins, MMPs and TIMPs, in human heart disease. We also discuss the role of TIMPs, MMPs, and a disintegrin and metalloproteinase (ADAMs) enzymes in cardiac development and function as learned through genetically altered mouse models.

scholarly journals LncRNA HBL1 is required for genome-wide PRC2 occupancy and function in cardiogenesis from human pluripotent stem cells

Development ◽  
2021 ◽  
Author(s):  
Juli Liu ◽  
Sheng Liu ◽  
Lei Han ◽  
Yi Sheng ◽  
Yucheng Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Transcription ◽  
Pluripotent Stem Cells ◽  
Cardiac Development ◽  
Chromatin Modification ◽  
Human Pluripotent Stem Cells ◽  
Cardiac Differentiation ◽  
Genome Wide ◽  
And Function

Polycomb Repressive Complex 2 (PRC2) deposits H3K27me3 on chromatin to silence transcription. PRC2 broadly interacts with RNAs. Currently, the role of RNA- PRC2 interaction in human cardiogenesis remains elusive. Here, we found human-specific Heart Brake LncRNA 1 (HBL1) interacted with two PRC2 subunits, JARID2 and EED, in human pluripotent stem cells (hPSCs). Loss-of-JARID2, EED or HBL1 significantly enhanced cardiac differentiation from hPSCs. HBL1 depletion disrupted genome-wide PRC2 occupancy and H3K27me3 chromatin modification on essential cardiogenic genes, and broadly enhanced cardiogenic gene transcription in undifferentiated hPSCs and later-on differentiation. Additionally, ChIP-seq revealed reduced EED-occupancy on 62 overlapped cardiogenic genes in HBL1−/- and JARID2−/- hPSCs, indicating the epigenetic state of cardiogenic genes was determined by HBL1 and JARID2 at pluripotency stage. Furthermore, after cardiac development occurred, the cytosolic and nuclear fractions of HBL1 could crosstalk via a conserved “microRNA-1-JARID2” axis to modulate cardiogenic gene transcription. Overall, our findings delineate the indispensable role of HBL1 in guiding PRC2 function during early human cardiogenesis, and expand the mechanistic scope of lncRNA(s) that cytosolic and nuclear portions of HBL1 could coordinate to orchestrate human cardiogenesis.

scholarly journals The Role of Tbx20 in Cardiovascular Development and Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuwen Chen ◽  
Deyong Xiao ◽  
Lu Zhang ◽  
Chen-Leng Cai ◽  
Bai-Yan Li ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Heart Function ◽  
Heart Defects ◽  
Transcriptional Networks ◽  
Complex Spectrum ◽  
Cardiovascular Development ◽  
T Box ◽  
Heart Arrhythmia ◽  
And Function

Tbx20 is a member of the Tbx1 subfamily of T-box-containing genes and is known to play a variety of fundamental roles in cardiovascular development and homeostasis as well as cardiac remodeling in response to pathophysiological stresses. Mutations in TBX20 are widely associated with the complex spectrum of congenital heart defects (CHDs) in humans, which includes defects in chamber septation, chamber growth, and valvulogenesis. In addition, genetic variants of TBX20 have been found to be associated with dilated cardiomyopathy and heart arrhythmia. This broad spectrum of cardiac morphogenetic and functional defects is likely due to its broad expression pattern in multiple cardiogenic cell lineages and its critical regulation of transcriptional networks during cardiac development. In this review, we summarize recent findings in our general understanding of the role of Tbx20 in regulating several important aspects of cardiac development and homeostasis and heart function.

scholarly journals GLUT12 deficiency during early development results in heart failure and a diabetic phenotype in zebrafish

2014 ◽  
Vol 224 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Vanesa Jiménez-Amilburu ◽  
Susanne Jong-Raadsen ◽  
Jeroen Bakkers ◽  
Herman P Spaink ◽  
Rubén Marín-Juez
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Developmental Stages ◽  
Cardiac Development ◽  
Number Of Genes ◽  
And Function ◽  
Early Developmental ◽  
Valve Formation

Cardiomyopathies-associated metabolic pathologies (e.g., type 2 diabetes and insulin resistance) are a leading cause of mortality. It is known that the association between these pathologies works in both directions, for which heart failure can lead to metabolic derangements such as insulin resistance. This intricate crosstalk exemplifies the importance of a fine coordination between one of the most energy-demanding organs and an equilibrated carbohydrate metabolism. In this light, to assist in the understanding of the role of insulin-regulated glucose transporters (GLUTs) and the development of cardiomyopathies, we have developed a model forglut12deficiency in zebrafish. GLUT12 is a novel insulin-regulated GLUT expressed in the main insulin-sensitive tissues, such as cardiac muscle, skeletal muscle, and adipose tissue. In this study, we show thatglut12knockdown impacts the development of the embryonic heart resulting in abnormal valve formation. Moreover,glut12-deficient embryos also exhibited poor glycemic control. Glucose measurements showed that these larvae were hyperglycemic and resistant to insulin administration. Transcriptome analysis demonstrated that a number of genes known to be important in cardiac development and function as well as metabolic mediators were dysregulated in these larvae. These results indicate thatglut12is an essential GLUT in the heart where the reduction in glucose uptake due toglut12deficiency leads to heart failure presumably due to the lack of glucose as energy substrate. In addition, the diabetic phenotype displayed by these larvae afterglut12abrogation highlights the importance of this GLUT during early developmental stages.

Mitochondria in Cardiomyopathy: Alterations in Size, Number and Internal Structures

1968 ◽  
Vol 26 ◽  
pp. 126-127
Author(s):  
George Hug ◽  
William K. Schubert
Keyword(s):  
Heart Failure ◽  
Biochemical Analysis ◽  
Left Ventricular ◽  
Size Number ◽  
Internal Structures ◽  
Left Ventricular Outflow ◽  
Chest X Ray ◽  
Myocardial Fibers ◽  
Muscle Biopsies ◽  
Needle Liver Biopsy

A white boy six months of age was hospitalized with respiratory distress and congestive heart failure. Control of the heart failure was achieved but marked cardiomegaly, moderate hepatomegaly, and minimal muscular weakness persisted.At birth a chest x-ray had been taken because of rapid breathing and jaundice and showed the heart to be of normal size. Clinical studies included: EKG which showed biventricular hypertrophy, needle liver biopsy which showed toxic hepatitis, and cardiac catheterization which showed no obstruction to left ventricular outflow. Liver and muscle biopsies revealed no biochemical or histological evidence of type II glycogexiosis (Pompe's disease). At thoracotomy, 14 milligrams of left ventricular muscle were removed. Total phosphorylase activity in the biopsy specimen was normal by biochemical analysis as was the degree of phosphorylase activation. By light microscopy, vacuoles and fine granules were seen in practically all myocardial fibers. The fibers were not hypertrophic. The endocardium was not thickened excluding endocardial fibroelastosis. Based on these findings, the diagnosis of idiopathic non-obstructive cardiomyopathy was made.

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