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.

• Authors: Maoqing Ye, Chris Coldren, Xingqun Liang, Teresa Mattina, Elizabeth Goldmuntz, D Woodrow Benson, Dunbar Ivy, M B Perryman, Lee Ann Garrett-Sinha, Paul Grossfeld
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 4 Pg. 648-56 (Feb 15 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 19942620 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Protein c-ets-1

Topics

• Animals
• Chromosome Deletion
• Chromosome Mapping
• Chromosomes, Human, Pair 11 (genetics)
• Gene Deletion
• Heart Septal Defects, Ventricular (embryology, genetics, metabolism)
• Heart Ventricles (abnormalities, embryology, metabolism)
• Humans
• Jacobsen Distal 11q Deletion Syndrome (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Proto-Oncogene Protein c-ets-1 (genetics, metabolism)