Elastin Gene Mutations: Mechanisms Causing SVAS and ADCL

描述(由申请人提供)：这项建议的总体目标是探索弹性蛋白基因(ELN)突变导致两种不同表型的人类遗传性疾病的不同病理机制：瓣膜上主动脉瓣上狭窄(SVAS)和常染色体显性遗传性皮肤松弛(ADCL)。在我们的初步数据中，我们提供的证据表明，SVAS中的阻塞性血管疾病是由弹性蛋白基因零突变引起的，由此导致的弹性蛋白沉积减少与过度增殖的细胞表型有关。相反，在ADCL患者中，我们发现了导致突变原弹性蛋白表达的突变。根据这些结果，我们推测，不同类型的弹性蛋白基因突变通过不同的病理机制扰乱弹性蛋白的生长调节或机械功能，从而导致SVAS和ADCL。为了验证这一假设，我们建议(1)对弹性蛋白基因(ELN)进行突变分析，并在一组SVAS和ADCL患者中进行基因-表型相关性研究；(2)对SVAS和ADCL突变导致的培养细胞中的突变进行功能分析；(3)通过在永生化色素上皮和皮肤成纤维细胞中表达野生型和突变型弹性蛋白微型基因，进一步进行功能研究；(4)通过将选定的突变弹性蛋白微型基因导入小鼠体内，建立ADCL的转基因模型。这里提出的研究利用了两种遗传病的独特存在，在这两种遗传病中，弹性蛋白的替代功能被ELN中不同类型的突变所破坏。因此，这些实验将允许基因解剖弹性蛋白在弹性组织中扮演的不同角色。我们的研究将有助于阐明SVAS和ADCL的发病机制，为更好地诊断和治疗这两种疾病提供依据。最后，我们期望更好地了解与ADCL相关的常见疾病的发病机制，如疝气、肺气肿和动脉瘤。

DESCRIPTION (provided by applicant): 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.