scholarly journals SHROOM3 is a novel component of the planar cell polarity pathway whose disruption causes congenital heart disease

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Alison Schmidt ◽  
Matthew Durbin, MS MD ◽  
James O’Kane, MS ◽  
Stephanie M. Ware, MD PHD
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Signaling Pathway ◽  
Cell Polarity ◽  
Congenital Heart ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Genetic Interaction ◽  
Compound Heterozygous ◽  
Pcp Signaling

Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite CHD frequency, the etiology remains mostly unknown. Understanding CHD genetics and elucidating disease mechanism will help establish prognosis, identify comorbidity risks, and develop targeted therapies. CHD often results from disrupted cytoarchitecture and signaling pathways. We have identified a novel CHD candidate SHROOM3, a protein associated with the actin cytoskeleton and the Wnt/Planar Cell Polarity (PCP) signaling pathway. SHROOM3 induces actomyosin constriction within the apical side of cells and is implicated in neural tube defects and chronic renal failure in humans. A recent study demonstrated that SHROOM3 interacts with Dishevelled2 (DVL2), a component of the PCP signaling pathway, suggesting that SHROOM3 serves as an important link between acto-myosin constriction and PCP signaling. PCP signaling establishes cell polarity required for multiple developmental processes, and is required for cardiac development. In Preliminary data we utilized a Shroom3 gene-trap mouse (Shroom3gt/gt) to demonstrated that SHROOM3 disruption leads to cardiac defects phenocopy PCP disruption. We also demonstrate that patients with CHD phenotypes have rare and potentially damaging SHROOM3 variants within SHROOM3’s PCP-binding domain. We hypothesize SHROOM3 is a novel terminal effector of PCP signaling, and disruption is a novel contributor to CHD. To test this, we assessed genetic interaction between SHROOM3 and PCP during cardiac development and the ultimate effect on cell structure and movement. Heterozygous Shroom3+/gt mice and heterozygous Dvl2 +/- mice are phenotypically normal. We demonstrated genetic interaction between SHROOM3 and PCP signaling by generating compound heterozygous Shroom3+/gt ;Dvl2 +/- mice and identifying a Double Outlet Right Ventricle and Ventricular Septal Defect in one embryo. We also observed fewer compound heterozygous mice than anticipated by Mendelian rations (observed: 18.4%; expected: 25%; n=76), suggesting potential lethality in utero. Immunohistochemistry demonstrates disrupted actomyosin in the SHROOM3gt/gt mice, characteristic of PCP disruption. These data help strengthen SHROOM3 as a novel CHD candidate gene and a component of the PCP Signaling pathway. Further characterization of this gene is important for CHD diagnosis and therapeutic development.

scholarly journals Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Gang Wu ◽  
Jiao Ge ◽  
Xupei Huang ◽  
Yimin Hua ◽  
Dezhi Mu
Keyword(s):  
Signaling Pathway ◽  
Cell Polarity ◽  
Congenital Heart ◽  
Planar Cell Polarity ◽  
Heart Diseases ◽  
Multiple Roles ◽  
Cardiac Differentiation ◽  
Tissue Polarity ◽  
Cardiac Disorder ◽  
Pcp Signaling

Congenital heart disease (CHD) is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification of many associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity inDrosophilaand gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD.

scholarly journals Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency

2021 ◽  
Vol 128 (8) ◽  
pp. 1156-1169
Author(s):  
Tarsha Ward ◽  
Warren Tai ◽  
Sarah Morton ◽  
Francis Impens ◽  
Petra Van Damme ◽  
...  
Keyword(s):  
Stem Cells ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Compound Heterozygous ◽  
Complex Activity ◽  
Induced Pluripotent

Rationale: NAA15 (N-alpha-acetyltransferase 15) is a component of the NatA (N-terminal acetyltransferase complex). The mechanism by which NAA15 haploinsufficiency causes congenital heart disease remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous loss of function, compound heterozygous, and missense residues (R276W) in iPSCs using CRISPR/Cas9. Haploinsufficient NAA15 iPSCs differentiate into cardiomyocytes, unlike NAA15 -null iPSCs, presumably due to altered composition of NatA. Mass spectrometry analyses reveal ≈80% of identified iPSC NatA targeted proteins displayed partial or complete N-terminal acetylation. Between null and haploinsufficient NAA15 cells, N-terminal acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W induced pluripotent stem cells. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; 18 were ribosomal-associated proteins. At least 4 proteins were encoded by genes known to cause autosomal dominant congenital heart disease. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and N-terminal acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated congenital heart disease. Additionally, genetically engineered induced pluripotent stem cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.

scholarly journals Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease

2020 ◽  
Author(s):  
Jennifer Romanowicz ◽  
Zaenab Dhari ◽  
Devon Guerrelli ◽  
Colm Mulvany ◽  
Marissa Reilly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Chronic Hypoxia ◽  
Cardiac Development ◽  
Contractile Function ◽  
Adverse Outcomes ◽  
Perinatal Hypoxia ◽  
Postnatal Environment

AbstractBackgroundCompared to acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development.MethodsMouse dams were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex-vivo electrophysiology study.ResultsHypoxic animals were 48% smaller than controls. Gene expression was grossly altered by hypoxia at P8 (1427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, which resolved after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, and a 24% reduction in contractile function in animals exposed to hypoxia.ConclusionsWe investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiologic substrate and contractile function warrant further investigation, and may contribute to adverse outcomes observed in the cyanotic CHD population.

Development of the ventricles and valves

ESC CardioMed ◽  
2018 ◽  
pp. 44-49
Author(s):  
José M. Pérez-Pomares ◽  
José L. de la Pompa
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Experimental Studies ◽  
Heart Tube ◽  
Cellular Mechanisms ◽  
Valve Development ◽  
Tissue Interactions ◽  
The Right

The heart is the first functional organ of the vertebrate embryo, beginning to beat at around 4 weeks of gestation in humans. Tissue interactions orchestrate the complex patterning, proliferation, and differentiation processes that transform the embryonic cardiac primordium into the adult heart. During heart embryogenesis, cardiac mesoderm progenitor cells originate bilaterally during gastrulation and move rostrally to form the primitive heart tube, which will then loop towards the right and initiate septation to give rise to the mature four-chambered heart. Experimental studies in animal models have revealed the crucial role that a number of highly conserved signalling pathways, involving active molecular cross-talk between adjacent tissues, play in cardiac development, and how the alterations in these signalling mechanisms may cause congenital heart disease affecting the neonate or adult. Here, we describe briefly the knowledge gained on the molecular and cellular mechanisms underlying cardiac chamber and valve development and its implication in disease. This knowledge will ultimately facilitate the design of diagnostic and therapeutic strategies to treat congenital heart disease.

scholarly journals Exploring the Role of Maternal Nutritional Epigenetics in Congenital Heart Disease

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Radha O Joshi ◽  
Subramanian Chellappan ◽  
Prachi Kukshal
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Mendelian Inheritance ◽  
Dietary Factors ◽  
Future Research ◽  
Epigenetic Programming ◽  
Periconceptional Period ◽  
Sporadic Cases

ABSTRACT Congenital heart disease (CHD) is one of the major debilitating birth defects resulting in significant impact on neonatal and child mortality globally. The etiology of CHD is complex and multifactorial. Many causative genes responsible for CHDs have been identified from the familial forms previously. Still, the non-Mendelian inheritance and predominant sporadic cases have stimulated research to understand the epigenetic basis and environmental impact on the incidence of CHD. The fetal epigenetic programming affecting cardiac development is susceptible to the availability of key dietary factors during the crucial periconceptional period. This article highlights the need and importance of in-depth research in the new emerging area of maternal nutritional epigenetics and CHD. It summarizes the current research and underlines the limitations in these types of studies. This review will benefit the future research on nutrition as a modifiable environmental factor to decrease the incidence of CHD.

Pitx2 and Cardiac Development: A Molecular Link between Left/Right Signaling and Congenital Heart Disease

2002 ◽  
Vol 67 (0) ◽  
pp. 89-96 ◽  
Author(s):  
M. CAMPIONE ◽  
L. ACOSTA ◽  
S. MARTINEZ ◽  
J.M. ICARDO ◽  
A. ARANEGA ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Cardiac Development
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