Molecular Genetic Basis of Williams Syndrome

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DESCRIPTION (provided by the applicant): Williams Syndrome (WS) is an autosomal dominant genetic condition characterized by an ensemble of physical, cognitive, and behavioral traits. The syndrome has been mapped to 7ql1.23, where genetic causation is attributed to a microdeletion of approximately 1.5 Mb in length. To date, 17 genes have been identified in the haplo-insufficiency region, which serve as specific candidates for the multiple features of the condition. While the 1.5 Mb deletion occurs most commonly, smaller more informative deletions occur at a lower frequency and facilitate the presumptive identification of genes that are causal to specific cranio-facial and neurological attributes of WS. Currently, deletion mapping implicates genes near the telomeric terminus of the deletion, as most critical in phenotype causation. Three genes are viable candidates. These are CLIP-115, BEN, and TFII-I. CLIP-115 is a cytoplasmic linker protein, while TFII-I and BEN are closely related helix-loop-helix transcription factors. We have recently isolated the BEN gene in mice in a search for factors that bind to the early enhancer of the developmentally important Hoxc8 gene. This implicates BEN and TFII-I as candidate developmental factors, deficiencies of which may be expected to generate the symptomology of WS. In an effort to establish the molecular basis of WS, we will use chromosome engineering and other transgenic methodologies to simulate a haplo-insufficiency for these three candidate genes in mice. The mutant mice will be examined for physical, biochemical, and behavioral phenotypes that are typical of persons with WS. In this way, we hope to implicate definitively the three candidate genes singly or in combination as casual factors in WS. This will represent the first step in establishing the molecular genetic basis of WS. The second step will involve the discovery of downstream genes regulated by the transcription factors BEN and TFII-I. We believe certain genes in this category may be profoundly deregulated in the WS haplo-insuficiency condition, and are therefore most probably the immediate causal factors in WS. The establishment of the developmental genetic basis of WS is important beyond the understanding it brings to WS itself. The identification of genes that regulate behavior allows further investigation of genetic polymorphisms of these genes that may be causal to less severe behavioral conditions or to variations in behavior within a range considered normal.