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doi:10.1534/genetics.105.054833
A more recent version of this article appeared on May 1, 2006.
REGULAR RESEARCH PAPERS |
A deficiency in the region homologous to human 17q21.33-q23.2 causes heart defects in mice
Y. Eugene Yu 1, Masae Morishima 2, Annie Pao 2, Ding-Yan Wang 3, Xiao-Yan Wen 3, Antonio Baldini 2 and Allan Bradley 4*
1 Roswell Park Cancer Institute
2 Baylor College of Medicine
3 University of Toronto
4 Wellcome Trust Sanger Institute
* To whom correspondence should be addressed. E-mail: abradley{at}sanger.ac.uk.
Submitted on December 17, 2005
Revised on January 17, 2006
Accepted on 14 February 2006
Several constitutional chromosomal rearrangements occur on human chromosome 17. Patients who carry constitutional deletions of 17q21.3-q24 exhibit distinct phenotypic features. Within the deletion interval, there is a genomic segment which is bounded by the myeloperoxidase and homeobox B1 genes. This genomic segment is syntenically conserved on mouse chromosome 11 and is bounded by the mouse homologs of the same genes (Mpo and HoxB1). To attain functional information about this syntenic segment in mice, we have generated a 6.9-Mb deletion [Df(11)18], the reciprocal duplication [Dp(11)18] between Mpo and Chad (the chondroadherin gene), and a 1.8-Mb deletion between Chad and HoxB1. Phenotypic analyses of the mutant mouse lines showed the Dp(11)18/Dp(11)18 genotype was responsible for embryonic or adolescent lethality, whereas the Df(11)18/+ genotype was responsible for heart defects. The cardiovascular phenotype of the Df(11)18/+ fetuses was similar to those of patients who carried the deletions of 17q21.3-q24. Since heart defects were not detectable in Df(11)18/Dp(11)18 mice, the haploinsufficiency of one or more genes that are located between Mpo and Chad may be responsible for the abnormal cardiovascular phenotype. Therefore, we have identified a new dosage-sensitive genomic region that may be critical for normal heart development in both mice and humans.
Key Words: Chromosome, Defects, Deletion, Heart, Mouse
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