Molecular genetics of Williams syndrome

Williams syndrome (WS) is a developmental disorder characterized by cardiovascular disease, connective tissue abnormalities, unique personality, specific cognitive profile, mental retardation, and infantile hypercalcemia. Over the past five years, our laboratory discovered that submicroscopic deletions of chromosome 7q11.23 cause WS and demonstrated the hemizygosity of two genes, elastin (ELN) and LIM-kinase (LILMK), is important for the WS phenotype. My contribution to these discoveries includes the following: mapping the locus for autosomal dominant supravalvular aortic stenosis (SVAS) to chromosome 7q11.23; identifying linkage between SVAS and ELN in two kindreds; demonstrating by Southern analyses that an SVAS-associated translocation disrupts ELN in a third kindred; identifying a ~90 kb SVAS-associated deletion in the 3' end of ELN in another kindred; demonstrating by dosage and genotype analyses that WS is caused by a submicroscopic deletion of chromosome 7q11.23 including one ELN allele; completing the characterization of the genomic structure of ELN for addition mutational analysis; and contributing to the finding that deletions of a second gene, LIMK are associated with specific cognitive profile of WS. These results provide the first molecular insight into the development of human cognitive function and the pathophysiology of ELN in vascular disease. Furthermore, these studies will facilitate future work deciphering the molecular basis of WS.