A deficiency in the region homologous to human 17q21.33-q23.2 causes heart defects in mice.
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 that 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 that 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 haplo-insufficiency of one or more genes 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.
Yu
Y Eugene
YE
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. yuejin.yn@roswellpark.org
Morishima
Masae
M
Pao
Annie
A
Wang
Ding-Yan
DY
Wen
Xiao-Yan
XY
Baldini
Antonio
A
Bradley
Allan
A
D000818:Animals; D018376:Cardiovascular Abnormalities / Q000235:genetics; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D033481:Chromosomes, Mammalian / Q000235:genetics*; D005313:Fetal Death / Q000235:genetics; D020440:Gene Duplication; D005819:Genetic Markers / Q000235:genetics; D016678:Genome / Q000235:genetics; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D011995:Recombination, Genetic; D012689:Sequence Homology, Nucleic Acid; D015996:Survival Rate; D026801:Synteny / Q000235:genetics*
D005819:Genetic Markers; D018398:Homeodomain Proteins