Williams syndrome (WS) is a developmental disorder with vascular, connective tissue, endocrine and central nervous system manifestations. WS is caused by a partial deletion of chromosome band 7q11.23 that involves the elastin gene and is estimated to be between 1 and 3 Mb in size. Complexity of the phenotype and size of the deletions suggest the pathogenetic involvement of contiguous genes yet to be identified. The deletion region will be physically defined by pulsed-field gel electrophoresis mapping and contig building of YAC, P1, PAC, BAC and cosmid clones using STS content mapping. Affinity capture, exon trapping, CpG island cloning and cDNA library screening will be used to identify new genes in the deletion. Functional domains will be identified by database sequence homology and expression patterns will be determined by Northern blotting and RT-PCR. Novel genes suspected of playing a regulatory role in development or of having a central nervous system or endocrine function will be targeted for detailed study, to include obtaining full-length cDNA sequence and genomic structure, identifying and mapping the mouse homologue and in situ hybridization on fetal tissues and mouse embryos. The relationship between size of the microdeletion and clinical phenotype will be examined by microsatellite marker testing of patients with variable expression of WS. Cis- and trans-acting regulatory effects of the deletion on the genome will be investigated through expression studies of the non-deleted alleles and neighboring genes. Models of gene interaction to be evaluated include additive effects of the loss of multiple genes, long-range effects on chromatin structure beyond the deletion, and gametic imprinting. The molecular mechanisms underlying deletion formation will be investigated. The hypothesis of low-copy number repeats flanking the deletion region and predisposing to errors in meiotic recombination will be tested through cloning of the common breakpoints. The identification of the genes whose haploinsufficiency underlies the WS phenotype, their interaction and effects on non-deleted genes, and detection of the mechanism underlying deletion formation will have implications for the development of new therapeutic modalities as well as provide insight into normal human developmental processes.
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