A number of human syndromes including DiGeorge (DGS), and Velocardiofacial syndromes are considered together as the 22q11 microdeletion syndromes based on the observation that the majority of cases arise from deletion of a common region of chromosome 22q11. Phenotypically these syndromes share one or more common features. However, the phenotypic severity varies tremendously even within syndromes, with no correlation evident with the extent of the deletion. At the present time the underlying genetic basis of these disorders remains unclear, and so to further a better understanding we plan to conduct a genetic dissection of these syndromes using the mouse as a model system. The contribution of individual genes such as Hira and Idd, which lie within the minimal deleted region in the human, are being determined by targeted gene disruption. This has been achieved in ES cells, and mice bearing these mutations are being generated for analysis. In addition, the region syntenic to a balanced translocation breakpoint in a human DGS family is being studied by the creation of a relatively small deletion of 140 Kb in the mouse. Mice bearing this deletion have been generated and their phenotype is under analysis. Finally, deletions of the same magnitude as those observed in the human 22q11 microdeletion syndromes, i.e. 2 Mb, are being created through the use of the loxP and Cre gene targeting strategy. LoxP sites have been targeted to various points in the mouse sytenic region, and exposure to the Cre protein should result in precise deletions of the desired size. Through comparison of the phenotypes expressed by these models, it may be possible to identify regions within 22q11 which have significance for the disease phenotype, and perhaps lead to the elucidation of the underlying genetic defect.
