Academic journal article Genetics

A Deficiency in the Region Homologous to Human 17q21.33-Q23.2 Causes Heart Defects in Mice

Academic journal article Genetics

A Deficiency in the Region Homologous to Human 17q21.33-Q23.2 Causes Heart Defects in Mice

Article excerpt

ABSTRACT

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 Bl 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 an 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.

THE most overt differences between the genomes of two mammalian species are the numbers and arrangement of their chromosomes. Structural alterations in the mammalian genome, particularly duplications and inversions, provide the raw material for the forces of evolution. Duplications enable genetic variants to be tested in one copy of a gene, enabling new gene functions to emerge, while inversions can lock sets of allelic variants into large haplotype blocks, enabling these to diverge as a group without genetic assortment until the inversion increases in frequency in the population.

Recently, it has been recognized that large genomic alterations involving loss or gain of millions of base pairs are common polymorphisms in the human and mouse populations (SEBAT et al. 2004; ADAMS et al. 2005). Most of these copy number polymorphisms (CNPs) do not have any developmental or physiological consequences to the individual with the CNP. However, a subset of these alterations are not neutral and are responsible for many disease processes. Chromosomal abnormalities in somatic cells play a major role in many types of cancer (RABBITTS 1994). Constitutional chromosomal abnormalities are important causes of human genetic diseases (SHAFFER and LUPSKI 2000). Some chromosomal rearrangements such as the deletions associated with DiGeorge, Prader-Willi/Angelman, Williams, and Smith-Magenis syndromes are generated de novo at a relatively high rate in the human population. Many other disease-associated chromosomal rearrangements have been described, but they are comparatively rare and/or their associated phenotypes are quite variable so that they have yet to be classified as "syndromes." Until recently, constitutional deletions have been identified using conventional cytogenetic techniques, restricting the detection limit of disease-associated deletions to several million base pairs. Recently, the use of high-resolution BAC arrays has begun to identify many more disease-associated deletions previously undetected because of the low resolution of cytogenetics. Characterization of these chromosomal rearrangements offers an opportunity to identify the causative genes for many disease phenotypes (RICCARDI et al. 1978; VARESCO et al. 1989; MILLAR et al. 2000).

The many conserved linkage groups between the genomes of humans and mice makes it possible to model the chromosomal rearrangements involved in human diseases by using chromosome engineering (RAMIREZ-SOLIS et al. 1995; YU and BRADLEY 2001). Mouse models that carry engineered chromosomal deletions have been successfully used to model the human chromosomal deletions that are responsible for DiGeorge syndrome (LINDSAY et al. …

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