WILLIAMS SYNDROME--MOLECULAR GENETIC CHARACTERIZATION

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We propose to begin to create links between Williams syndrome (WMS), a rare genetic disorder that typically results in mental retardation, a distinctive facies and a heart defect, its cognitive sequellae and its genetic basis. In most cases, WMS is associated with a hemizygous deletion around the elastin gene on chromosome band 7q11.2. To ultimately identify the pathway from genes to cognition in WMS, we will carefully define the genetic regions deleted in the patients studied in projects I-III. Because the expression of genes located near the deletion may also be affected and contribute to the phenotype, the genetic structure of the flanking regions will also be determined. To obviate the deficiencies of the current physical map of the WMS region in yeast artificial chromosomes (YACs), an independent approach employing bacterial artificial chromosomes (BACs) will be used. Established as an ideal tool for molecular cytogenetics, genome mapping and sequencing, an array of 50 BACs has been defined that map within and flanking the WMS region. Using these, a portion of the WMS deleted region has now been cloned, the approximate size of the common deletions has been estimated, BACs closely flanking the deletion have been identified; and 4) A novel family of repeated sequences mapping only in this chromosome band has been identified that may be ultimately responsible for causing the WMS deletion. The project is organized into four aims. Aim 1: A physical map of the WMS region will be constructed in BACs and PACs using end clone walking, PCR, and clone to clone Southern analysis. Aim 2: A critical region likely to contain the genes responsible for the WMS cognitive phenotype will be defined by using fluorescence in situ hybridization of BACs (bacterial artificial chromosomes) and PACs (PI artificial chromosomes), Southern blot dosage analysis of single copy DNA markers, and PCR analyses of polymorphic markers. Aim 3: The molecular data will then be combined with the clinical and neurocognitive data from projects I-IV to generate a Phenotypic Map of WMS, to define molecularly, the regions of chromosome 7q11.23 that are likely to contain the genes for some of the physical and metabolic features, and a part of the mental retardation and cognitive features. Aim 4: The genes mapping in these regions will be isolated by cDNA selection and characterized. The results of this work will lay the groundwork for elucidating the common genetic origins of cognition.