Autosomal dominant cutis laxa with severe lung disease: Synthesis and matrix deposition of mutant tropoelastin
Autosomal dominant cutis laxa with severe lung disease: Synthesis and matrix deposition of mutant tropoelastin
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DOI：
10.1111/j.0022-202x.2005.23758.x
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发表时间：
2005-06-01
影响因子：
6.5
通讯作者：
Davis, EC
中科院分区：
文献类型：
--
作者：
Urban, Z;Gao, JM;Davis, EC
皮肤松弛症（CL）是遗传性和获得性疾病的异质性群体，至少有两种常染色体显性形式，分别由弹性蛋白和纤维蛋白-5基因突变引起。为了明确弹性蛋白基因点突变阴性患者CL的分子基础，我们采用代谢标记和免疫沉淀实验研究了真皮成纤维细胞中弹性蛋白的合成。除了正常的68 kDa的tropoelastin （TE）蛋白外，在先证者及其受影响的女儿的CL家族中检测到异常的120 kDa多肽，其特征是疝气和异常严重的早发性肺部疾病，包括支气管扩张和肺气肿。突变和基因表达研究证实，该家族中受影响的个体在弹性蛋白位点上携带部分串联重复。免疫沉淀实验表明，突变TE部分分泌，部分保留在细胞内。针对突变TE分子中独特肽的多克隆抗体显示细胞内和基质染色。我们得出结论，弹性蛋白突变可导致CL与严重的肺表型相关。异常TE的合成可能通过显性负性或增益性机制干扰弹性纤维的功能。
Cutis laxa (CL) is a heterogeneous group of genetic and acquired disorders with at least two autosomal dominant forms caused by mutations in the elastin and fibulin-5 genes, respectively. To define the molecular basis of CL in patients negative for point mutations in the elastin gene, metabolic labeling and immunoprecipitation experiments were used to study the synthesis of elastin in dermal fibroblasts. In addition to the normal 68 kDa tropoelastin (TE) protein, an abnormal, 120 kDa polypeptide was detected in the proband and her affected daughter in a CL family characterized by hernias and unusually severe and early-onset pulmonary disease including bronchiectasis and pulmonary emphysema. Mutational and gene expression studies established that affected individuals in this family carried a partial tandem duplication in the elastin locus. Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly. A polyclonal antibody raised against a unique peptide in the mutant TE molecule showed both intracellular and matrix staining. We conclude that elastin mutations can cause CL associated with a severe pulmonary phenotype. Synthesis of abnormal TE may interfere with elastic fiber function through a dominant-negative or a gain of function mechanism.