The Williams-Beuren Syndrome—A Window into Genetic Variants Leading to the Development of Cardiovascular Disease

Abstract

Williams-Beuren Syndrome (WBS) arises when there is a genomic microdeletion at human chromosome 7q11.23 (Mouse 5G2), resulting in various cardiovascular, developmental, metabolic, and mental disorders [1]. Cardiovascular complications from WBS are a frequent cause of death. The deleted region is predisposed to non-allelic homologous recombination (NAHR) due to the presence of repetitive DNA regions called segmental duplications. WBS can result in deletions of up to 1.83 Mb in a region containing roughly 28 genes that includes the gene ELN encoding the tissue structural protein elastin [2]. Many of the cardiovascular features of WBS can be partially explained by elastin defects. WBS individuals have a combined prevalence of cardiovascular disease of 84% that includes supraand sub-aortic stenosis (SVAS); aortic, pulmonary, and mitral valvular disease; aortic coarctation; hypertension; and, less commonly, myocardial infarction [2,3]. These defects have also been found in mouse models [4]. Elastin not only provides ‘‘elastic’’ support for vessels, it also serves as a negative regulator for smooth muscle cell proliferation. WBS patients are also at high risk for hypertension and Eln mice are hypertensive [1,4]. In 2006, Del Campo et al. recognized that hemizygosity of the NCF1 gene as a result of the largest recognized WBS microdeletion—about 1.83 Mb—decreases the risk for hypertension in WBS patients compared to those possessing the more common smaller deletion (1.55 Mb) not incorporating NCF1 (Figure 1, top) [5]. NCF1 codes for p47, a critical subunit in the assembly of NADPH oxidase (NOX); homozygous deficiency accounts for 20% of patients with chronic granulomatous disease, a disorder associated with repeated infections due to an inability to kill bacteria. p47 is a major effector of angiotensin II (AngII), as demonstrated by a lack of elevation in blood pressure of Ncf1 mice [6]. In this issue of PLoS Genetics, Campuzano and colleagues replicate the WBS cardiovascular phenotype in a WBS mouse model with and without a deletion of the Ncf1 gene [7]. Their study has broad implications for our understanding of hypertensionand reactive oxygen species (ROS)-related cardiovascular disease.