The overall goal of this proposal is to explore the functionally distinct pathomechanisms by which mutations in the elastin gene (ELN) result in the two phenotypically different heritable human disorders, supravalvular aortic stenosis (SVAS) and autosomal dominant cutis laxa (ADCL). In our preliminary data we provide evidence indicating that obstructive vascular disease in SVAS is caused null mutations in the elastin gene and that the resulting reduction of elastin deposition is associated with a hyperproliferative cellular phenotype. In ADCL patients, in contrast, we have identified mutations that result in the expression of mutant tropoelastin. Based on these results, we hypotesize that different classes of elastin gene mutations result in SVAS and ADCL by disrupting either the growth regulatory or the mechanical function of elastin through distinct pathomech an isms. To test this hypothesis, we propose (1) a mutational analysis of the elastin gene (ELN) and genotype-phenotype association studies in a cohort of SVAS and ADCL patients, (2) functional analysis of the mutations in cultured cells form SVAS and ADCL mutations, (3) further functional studies by expressing wild type and mutant elastin minigenes in immortalized pigment epithelium and skin fibroblast cells and (4) generation of a transgenic model of ADCL by introducing selected mutant elastin minigenes into mice. The studies proposed here take advantage of the unique existence of two genetic disorders in which alternative functions of elastin are disrupted by different types of mutations within ELN. These experiments therefore will allow for the genetic dissection of the different roles elastin plays in elastic tissue. Our studies will lead to the elucidation of the pathomechanism of SVAS and ADCL which may be used for better diagnosis and treatment of these diseases. Finally, we expect to gain a better understanding of the pathomechanisms of common diseases that are found in association with ADCL such as hernias, emphysema and arterial aneurysms.
| Jelsig, Anne Marie; Urban, Zsolt; Hucthagowder, Vishwanathan et al. (2017) Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm. Eur J Med Genet 60:110-113 |
| Berk, David R; Bentley, Danette D; Bayliss, Susan J et al. (2012) Cutis laxa: a review. J Am Acad Dermatol 66:842.e1-17 |
| Hu, Qirui; Shifren, Adrian; Sens, Carla et al. (2010) Mechanisms of emphysema in autosomal dominant cutis laxa. Matrix Biol 29:621-8 |
| Nonaka, Risa; Onoue, Satoshi; Wachi, Hiroshi et al. (2009) DANCE/fibulin-5 promotes elastic fiber formation in a tropoelastin isoform-dependent manner. Clin Biochem 42:713-21 |
| Morava, E; Lefeber, D J; Urban, Z et al. (2008) Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. Eur J Hum Genet 16:28-35 |
| Wachi, Hiroshi; Sato, Fumiaki; Nakazawa, Junji et al. (2007) Domains 16 and 17 of tropoelastin in elastic fibre formation. Biochem J 402:63-70 |
| Tassabehji, May; Urban, Zsolt (2006) Congenital heart disease: Molecular diagnostics of supravalvular aortic stenosis. Methods Mol Med 126:129-56 |
| Hu, Qirui; Loeys, Bart L; Coucke, Paul J et al. (2006) Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa. Hum Mol Genet 15:3379-86 |
| Hucthagowder, Vishwanathan; Sausgruber, Nina; Kim, Katherine H et al. (2006) Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet 78:1075-80 |
| Hu, Qirui; Reymond, Jean-Louis; Pinel, Nicole et al. (2006) Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol 126:283-90 |
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