To characterize genetic variation that impacts the severity of blood vessel disease in patients with elastin insufficiency and Williams syndrome, we are using a combination of approaches. First, using a technique called quantitative trait locus analysis, we identified different regions of the mouse genome where differences in genetic background impact the degree of hypertension and vascular narrowing in Eln+/- mice. Subsequent work has identified distinct genetic modifiers from under two of those peaks (Ren1 and Ncf1) with an additional genomic region on chromosome 2 near the Fbn1 and Jag1 genes. With the identification of these modifiers, further study into the mechanism of action and potential therapeutic value can be undertaken. Work this year has focused on understanding the mechanism by which the renin angiotensin system and NADPH oxidases contribute to hypertension in elastin insufficiency. Secondly, we have acquired tissue samples from individuals with WS that have severe arteriopathy and from those with more mild cardiovascular features. By growing those tissues and studying the differences between the two groups (gene expression, rate of proliferation, etc), genes and pathways can be identified that differentiate the two. Such work can be done in the fibroblasts themselves or by turning the cells into smooth muscle cells by the production of induced pluripotent stem cells (IPSC). To date, we have generated multiple IPSC lines and have successfully derived smooth muscle cells that deposit elastin. Work this year has focused on understanding the process of elastic fiber assembly and has shown that successful elastin deposition only occurs after cells begin producing the full set of elastin assembly molecules including fibulins-4 and 5 and lysyl oxidase. Finally, we are looking at the association of rare and common genomic variants with disease severity in WS patients. Toward this end, we have collected questionnaire data, medical records and DNA on more than 180 individuals with Williams Beuren syndrome. WBS deletion size was determined for each subject. We subsequently performed exome sequencing and began to compare genetic variants between those with mild disease and those with a more severe phenotype. To optimize power, we focused our analysis on candidate genes and pathways identified from information in the literature or from our animal and cell studies. Our first manuscript looking at variation in genes that impact social behavioral features in WBS was submitted to the American Journal of Medical Genetics in July 2017. We are also completing an analysis on variation in cardiovascular disease that rules out the remaining elastin allele as well as variation within the WBS locus (other than NCF1 copy number) as major contributors to SVAS or hypertension. Further work evaluating cardiovascular disease will focus on genes outside the WBS deletion in pathways related to extracellular matrix, cell matrix interaction and cell proliferation. Taken together, these three complimentary projects will allow us to identify important pathways that interact with elastin insufficiency to produce clinical disease.
| Kopp, Nathan D; Parrish, Phoebe C R; Lugo, Michael et al. (2018) Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior. Mol Genet Genomic Med 6:749-765 |
| Duque Lasio, Maria Laura; Kozel, Beth A (2018) Elastin-driven genetic diseases. Matrix Biol : |
| Baldridge, Dustin; Heeley, Jennifer; Vineyard, Marisa et al. (2017) The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. Genet Med 19:1040-1048 |
