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Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice.

ABSTRACT: Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, including an unprecedented high frequency of hypoplastic left heart syndrome (HLHS). We identified an approximately 7 Mb 'cardiac critical region' in distal 11q that contains a putative causative gene(s) for congenital heart disease. In this study, we utilized chromosomal microarray mapping to characterize three patients with 11q- and congenital heart defects that carry interstitial deletions overlapping the 7 Mb cardiac critical region. We propose that this 1.2 Mb region of overlap harbors a gene(s) that causes at least a subset of the congenital heart defects that occur in 11q-. We demonstrate that one gene in this region, ETS-1 (a member of the ETS family of transcription factors), is expressed in the endocardium and neural crest during early mouse heart development. Gene-targeted deletion of ETS-1 in mice in a C57/B6 background causes, with high penetrance, large membranous ventricular septal defects and a bifid cardiac apex, and less frequently a non-apex-forming left ventricle (one of the hallmarks of HLHS). Our results implicate an important role for the ETS-1 transcription factor in mammalian heart development and should provide important insights into some of the most common forms of congenital heart disease.

SUBMITTER: Ye M

PROVIDER: S-EPMC2807373 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice.

Ye Maoqing M Coldren Chris C Liang Xingqun X Mattina Teresa T Goldmuntz Elizabeth E Benson D Woodrow DW Ivy Dunbar D Perryman M B MB Garrett-Sinha Lee Ann LA Grossfeld Paul P

Human molecular genetics 20091126 4

Congenital heart defects comprise the most common form of major birth defects, affecting 0.7% of all newborn infants. Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal 11q. We have previously determined that a wide spectrum of the most common congenital heart defects occur in 11q-, including an unprecedented high frequency of hypoplastic left heart syndrome (HLHS). We identified an approximately 7 Mb 'cardiac critical region' in distal 11q that contains a puta ...[more]

PMID: 19942620

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Project description:Surgical septal myectomy is increasingly utilized for patients with hypertrophic obstructive cardiomyopathy who remain symptomatic despite maximum doses of medical therapy. Deep and extensive septal muscle resections may lead to iatrogenic ventricular septal defects that are detected on transesophageal echocardiography immediately after weaning from cardiopulmonary bypass and immediately corrected in the same surgery. However markedly thinned out ventricular septum after myectomy may be prone to late rupture from high left ventricular systolic pressures causing delayed detection of a ventricular septal defect when the patients present with new onset symptoms. Additionally, a surgical injury to the first septal perforator artery during the myocardial resection leading to septal infarction may contribute to delayed occurrence of ventricular septal defect. Such a predisposing deep septal resection or septal infarction may be associated with varying degrees of atrioventricular nodal block warranting a permanent pacing. A new onset interventricular shunt from such an iatrogenic ventricular septal defect often leads to heart failure as the filling pressures increase disproportionately in the thick hypertrophied left ventricle. Transcatheter closure is an alternative to a high-risk repeat surgery. This report of device closure of two delayed septal ruptures after myectomy discusses the reasons, presentation, catheter approaches, and procedural challenges. <Learning objective: Deep extended septal myectomy for medically refractory hypertrophic obstructive cardiomyopathy may lead to early or late iatrogenic ventricular septal defect. Such an extensive loss of septal muscle may be additionally indicated by co-occurrence of atrioventricular nodal block that needs permanent pacing. Heart failure from the new onset interventricular shunt is not clinically tolerated by the hypertrophied left ventricle due to elevated end diastolic pressures. Transcatheter closure of the ventricular septal defect is an attractive alternative to a morbid repeat surgery.>.

Dataset Information

Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice.

Publications

Deletion of ETS-1, a gene in the Jacobsen syndrome critical region, causes ventricular septal defects and abnormal ventricular morphology in mice.

Similar Datasets

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