title: Mouse models of genetic diseases resulting from mutations in elastic fiber proteins.
abstract: 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.
authors.affiliation: 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. hdietz@welchlink.welch.jhu.edu
authors.forename: H C
authors.initials: HC
authors.lastname: Dietz
authors.forename: R P
authors.initials: RP
authors.lastname: Mecham
mesh_terms: D000818:Animals; D021921:Aortic Stenosis, Supravalvular / Q000235:genetics / Q000503:physiopathology; D003240:Connective Tissue Diseases / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D004549:Elastin / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D054392:Adipokines
chemical_list: D004549:Elastin; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse