Mutations of extracellular matrix components in vascular disease

Background. Marfan's syndrome (MFS) is characterized by manifestations in the skeletal, ocular, and cardiovascular systems. Dilatation of the aortic root is the hallmark feature in the cardiovascular system. Aortic dilatation is associated with fragmented elastic fibers and accumulation of amorphous matrix elements in the medial layer. This pathology is caused by mutations in fibrillin 1, the major structural component of elastic microfibrils. Fibrillin 1 mutations may affect the assembly or function of the elastic microfibrils or both. To answer this important question, MFS-like mice have been created. Methods. MFS-like mice were generated by homologous gene targeting in embryonic stem cells. Targeting of the mouse fibrillin 1 gene had the dual effect of reducing gene expression 10-fold and of producing an internally deleted protein. Results. Mutant homozygous mice make very small amounts of only mutant fibrillin 1 and die postnatally of MFS-like vascular complications. Histopathological findings include focal fragmentation of elastic fibers and accumulation of amorphous matrix in the aortic media. Conclusions. A mouse model for the severe form of MFS has been created using the technique of gene targeting. Aside from its clinical value, the model has demonstrated that fibrillin 1 is predominantly involved in the function rather than the assembly of elastic microfibrils.