The hemizygous deletion of a chromosomal region of human 22q11 is the genetic basis for several developmental defects with variable clinical severity. The clinical presentations may fit the diagnostic criteria for DiGeorge syndrome (DGS), Velocardiofacial syndrome (VCFS) or be very mild or complex. Approximately 80% of patients with a 22q11 deletion (de122q11) presents with a congenital heart defects, mostly of conotruncal origin and affecting the outflow tract of the heart. Heart defects represent the most dramatic clinical findings and are responsible for virtually all the early deaths in these patients. As the 22q11 deletion is one of the most frequent chromosomal deletions associated with an anomalous phenotype known in humans, this genetic lesions represents an important cause of heart defects. Furthermore, we have shown that for certain specific defects, such as interrupted aortic arch type B, the deletion is found in 50% of the cases, hence representing a major genetic cause for this anomaly. A 'critical region' the deletion of which is sufficient to produce the de122q11 phenotype has been delineated. As of today, at least 9 genes have been identified in this 300-400 kb interval. However, it is still unknown whether or not any of these genes is etiologically important for the phenotype or whether this is a single or multiple gene defect. We propose a novel and powerful approach for the modeling of this important deletion syndrome. We will use chromosome engineering to generate mouse deletions which simulate the human deletion. Deletions will be generated using the Cre-loxP strategy in embryonic stem (ES) cells. Mice carrying the deficiencies will be obtained to test the phenotypic effects of the deficiencies. Transgenic rescue experiments will be performed to complement in vivo the deficiencies and identify a genomic segment sufficient to rescue the phenotype. With these approaches we will be able to dissect genetically the mechanisms which lead to the developmental heart defects typical of the de122q11 phenotype.

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National Heart, Lung, and Blood Institute (NHLBI)
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Baylor College of Medicine
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