Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome
Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome
复制标题
DOI：
10.1172/jci200420641
复制
发表时间：
2004-07-01
影响因子：
15.9
通讯作者：
Dietz, HC
中科院分区：
文献类型：
--
作者：
Judge, DP;Biery, NJ;Dietz, HC
马凡氏综合征是一种结缔组织疾病，由编码β-淀粉样蛋白-1（FBN 1）的基因突变引起。基于显性遗传、形成微纤维的单体的多聚化以及杂合患者样品中观察到的基质掺入的Riskin-1的显著缺乏，已经推断出显性-负性机制。基于酵母人工染色体的转基因用于在正常小鼠背景上过表达疾病相关的突变形式的人白细胞介素-1（C1663 R）。值得注意的是，这些小鼠未能显示出任何细胞或临床表型的异常，尽管在相关组织和发育阶段中突变蛋白的过表达受到调节，并且直接证据表明小鼠和人的Escherin-1以高效率相互作用。免疫染色与人类特异性单克隆抗体提供了什么，我们认为是第一次证明突变体的repeatin-1可以参与生产性微纤维组装。从信息上讲，使用同源重组产生具有可比错义突变（C1039 G）的杂合子小鼠，发现微纤维沉积受损、骨骼畸形和主动脉壁结构进行性恶化，与人类疾病特征相当。这些数据是一致的模型，调用单倍不足的野生型β-内酰胺酶-1，而不是生产的突变蛋白，作为失败的微纤维组装的主要决定因素。与该模型一致，在杂合C1039 G背景上引入WT FBN 1转基因挽救了主动脉表型。
Marfan syndrome is a connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1). A dominant-negative mechanism has been inferred based upon dominant inheritance, mulitimerization of monomers to form microfibrils, and the dramatic paucity of matrix-incorporated fibrillin-1 seen in heterozygous patient samples. Yeast artificial chromosome-based transgenesis was used to overexpress a disease-associated mutant form of human fibrillin-1 (C1663R) on a normal mouse background. Remarkably, these mice failed to show any abnormalities of cellular or clinical phenotype despite regulated overexpression of mutant protein in relevant tissues and developmental stages and direct evidence that mouse and human fibrillin-1 interact with high efficiency. Immunostaining with a human-specific mAb provides what we believe to be the first demonstration that mutant fibrillin-1 can participate in productive microfibrillar assembly. Informatively, use of homologous recombination to generate mice heterozygous for a comparable missense mutation (C1039G) revealed impaired microfibrillar deposition, skeletal deformity, and progressive deterioration of aortic wall architecture, comparable to characteristics of the human condition. These data are consistent with a model that invokes haploinsufficiency for WT fibrillin-1, rather than production of mutant protein, as the primary determinant of failed microfibrillar assembly. In keeping with this model, introduction of a WT FBN1 transgene on a heterozygous C1039G background rescues aortic phenotype.