IDENTIFICATION OF THE GENE(S) RESPONSIBLE FOR ALAGILLE SYNDROME

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Alagille syndrome is an autosomal dominant disorder affecting liver, heart, vertebrae, eyes and faces. The locus for the AGS has been mapped to a 1,300 kb interval defined by STSs D20S189 and D20S162 at 20p12. We have constructed a bacterial clone contig consisting of BAC and PAC clones for the AGS region. Our efforts to construct a transcript map of this region have resulted in the identification of two transcripts. Based on the sequence homology to a CpG island, a homologue of a rat gene has been identified. The full length cDNA (6 kb) has been isolated and sequenced including a 5' promoter region of about 2.5 kb. In addition, we identified two ESTs in the AGS region from a total of 38 ESTs mapped to chromosome 20. One of them is part of a well characterized neuron specific gene (SNAP25). Efforts are being made to identify all the transcripts in the AGS interval. The clones from the contig will be used to identify submicroscopic deletions to narrow the AGS region. The SNAP25, the human homolog of the rat gene and all the other genes identified will be subjected to mutational analysis by Southern, Northern, SSCP/ddF methods in order to identify the gene(s) responsible for AGS.