Dietz H C, Mecham R P
Departments of Pediatrics, Medicine, and Molecular Biology and Genetics, and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Ross 858, 720 Rutland Ave., Baltimore, MD 21205, USA.
Matrix Biol. 2000 Nov;19(6):481-8. doi: 10.1016/s0945-053x(00)00101-3.
The inability to study appropriate human tissues at various stages of development has precluded the elaboration of a thorough understanding of the pathogenic mechanisms leading to diseases linked to mutations in genes for elastic fiber proteins. Recently, new insights have been gained by studying mice harboring targeted mutations in the genes that encode fibrillin-1 and elastin. These genes have been linked to Marfan syndrome (MFS) and supravalvular aortic stenosis (SVAS), respectively. For fibrillin-1, mouse models have revealed that phenotype is determined by the degree of functional impairment. The haploinsufficiency state or the expression of low levels of a product with dominant-negative potential from one allele is associated with mild phenotypes with a predominance of skeletal features. Exuberant expression of a dominant-negative-acting protein leads to the more severe MFS phenotype. Mice harboring targeted deletion of the elastin gene (ELN) show many of the features of SVAS in humans, including abnormalities in the vascular wall and altered hemodynamics associated with changes in wall compliance. The genetically altered mice suggest that SVAS is predominantly a disease of haploinsufficiency. These studies have underscored the prominent role of the elastic matrix in the morphogenesis and homeostasis of the vessel wall.
无法在发育的各个阶段研究合适的人体组织，这妨碍了人们对导致与弹性纤维蛋白基因突变相关疾病的致病机制形成透彻的理解。最近，通过研究在编码原纤蛋白-1和弹性蛋白的基因中携带靶向突变的小鼠，人们获得了新的见解。这些基因分别与马凡综合征（MFS）和瓣膜上主动脉狭窄（SVAS）有关。对于原纤蛋白-1，小鼠模型显示表型由功能受损程度决定。单倍剂量不足状态或一个等位基因表达具有显性负性潜能的低水平产物与以骨骼特征为主的轻度表型相关。显性负性作用蛋白的过度表达会导致更严重的MFS表型。携带弹性蛋白基因（ELN）靶向缺失的小鼠表现出人类SVAS的许多特征，包括血管壁异常以及与壁顺应性变化相关的血流动力学改变。基因改变的小鼠表明，SVAS主要是一种单倍剂量不足的疾病。这些研究强调了弹性基质在血管壁形态发生和内环境稳定中的重要作用。
