Elastin Gene Mutations: Mechanisms Causing SVAS and ADCL

描述（由申请人提供）：本提案的总体目标是探索弹性蛋白基因（ELN）突变导致两种表型不同的遗传性人类疾病，即瓣上主动脉瓣狭窄（SVAS）和常染色体显性皮肤松弛症（ADCL）的功能不同的病理机制。在我们的初步数据中，我们提供的证据表明，SVAS的阻塞性血管疾病是由弹性蛋白基因的零突变引起的，由此导致的弹性蛋白沉积的减少与过度增生的细胞表型有关。相反，在ADCL患者中，我们已经确定了导致突变的tropoelastin表达的突变。基于这些结果，我们假设不同类型的弹性蛋白基因突变通过不同的病理机制破坏弹性蛋白的生长调节或机械功能而导致SVAS和ADCL。为了验证这一假设，我们提出(1)在SVAS和ADCL患者队列中对弹性蛋白基因（ELN）进行突变分析和基因型-表型关联研究，(2)对SVAS和ADCL突变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，进一步研究其功能；(4)通过将选择的突变型弹性蛋白引入小鼠体内，建立ADCL转基因模型。这里提出的研究利用了两种遗传疾病的独特存在，其中弹性蛋白的替代功能被ELN内不同类型的突变破坏。因此，这些实验将允许对弹性蛋白在弹性组织中扮演的不同角色进行遗传解剖。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些疾病提供依据。最后，我们希望更好地了解与ADCL相关的常见疾病（如疝、肺气肿和动脉动脉瘤）的病理机制。

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.