GENES FROM DEL22Q11 INVOLVED IN HEART DEVELOPMENT

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DESCRIPTION (Adapted from investigator's abstract): This is a revised RO1 application for four years of support to identify genes in mice responsible for congenital heart disease associated with the human 22qdel syndrome. The PI has recently demonstrated that an approximately 1 Mb Cre-mediated deletion that extends between Ufd1l and Es2 causes abnormalities of 4th aortic arch derivatives very similar to those found in humans with the common 22q deletion. A duplication of the same region-recovered as a reciprocal recombination product between tandem lox sites-prevents cardiac abnormalities in duplication/deficiency heterozygotes, suggesting that haploinsufficiency for a gene or genes within the deletion is responsible for the characteristic cardiac defect. Preliminary data obtained with additional deficiencies since the last submission suggests that the sequence necessary for the 4th arch abnormality lies within a 150 kb "critical region" and that complementation with a slightly larger region would be sufficient to rescue that abnormality. The sequence of the entire region has been determined. In the current application, the PI proposes to test for complementation 3 BAC or PAC clones that span the region (Aim 1). Individual candidates within a complementing BAC will be evaluated by gene targeting (Aim 2), and function of correct candidate will be investigated further by analyzing the homozygous mutant phenotype, possibly in the context of a conditional allele.