Williams syndrome is a genetic condition caused by the deletion of 26-28 contiguous genes, including elastin, on the 7th human chromosome. Its findings include characteristic facial features, a gregarious personality, and stenoses in major conducting blood vessels, among other features. Previous work has shown that decreased elastin deposition is responsible for the vascular abnormalities in these individuals and in others with non-syndromic supravalvular aortic stenosis (SVAS). However, not every patient with Williams syndrome or SVAS has vascular abnormalities. In fact, the spectrum of vascular disease in this group is quite variable, with 30% requiring surgical intervention in the first several years due to severe stenosis or other abnormalities and 20% having no vascular abnormalities at all. The remaining patients have more mild vascular disease. The goal of the research in the Kozel laboratory is to identify the genetic and environmental factors responsible for this variability so as to influence the treatment of patients with these conditions.
To answer these questions, our lab studies both humans and mice with elastin insufficiency:
- Elastin insufficiency animal model: Using a mouse that is deficient in elastin, the Eln+/- mouse, we are using genetic screens (quantitative trait locus (QTL) mapping) to identify modifiers of elastin insufficiency. Our first screen identified multiple highly significant peaks related to the severity hypertension and vascular narrowing seen in the Eln+/-. Current work is aimed at identifying genes under those peaks responsible for these phenotypes and has suggested a role for the renin-angiotensin-NAPDH oxidase system and the generation of oxidative stress in modifying the severity of vascular disease in these animals.
- WS-SAVE study: We are working to extend the hypotheses generated in our mouse model to humans with Williams syndrome. Work in this area is aimed at using non-invasive methods such as pulse wave velocity and skin elasticity measurements to characterize tissue elasticity in this cohort. Using next-gen sequencing of DNA samples from individuals with Williams syndrome, we are looking for changes in the mutation burden in pathways identified in our mouse model between individuals with more and less severe vascular disease.
- Williams syndrome DNA and Tissue Bank. To further understand the natural history of Williams syndrome and to learn about the person to person variability in syndrome features, we are collecting medical history, DNA and sometimes tissue samples from individuals with WS. We plan to use this data to identify important differences in DNA or exposures that may contribute to this variability in many Williams associated conditions. Current work with these samples involves differences in severity of blood vessel disease but we hope to use these samples to study many more aspects of WS down the line.
If you are interested in participating in research studies related to WS, please contact our study coordinator, Joshua Danback at 314-286-1693.
Work in the Kozel Lab is supported by the National Institutes of Health, the Child Health Research Center at Washington University, and The Children's Discovery Institute.