Abstract-Diseases linked to the elastin gene arise from loss-of-function mutations leading to protein insufficiency (supravalvular aortic stenosis) or from missense mutations that alter the properties of the elastin protein (dominant cutis laxa). Modeling these diseases in mice is problematic because of structural differences between the human and mouse genes. To address this problem, we developed a humanized elastin mouse with elastin production being controlled by the human elastin gene in a bacterial artificial chromosome. The temporal and spatial expression pattern of the human transgene mirrors the endogenous murine gene, and the human gene accurately recapitulates the alternative-splicing pattern found in humans. Human elastin protein interacts with mouse elastin to form functional elastic fibers and when expressed in the elastin haploinsufficient background reverses the hypertension and cardiovascular changes associated with that phenotype. Elastin from the human transgene also rescues the perinatal lethality associated with the null phenotype. The results of this study confirm that reestablishing normal elastin levels is a logical objective for treating diseases of elastin insufficiency such as supravalvular aortic stenosis. This study also illustrates how differences in gene structure and alternative splicing present unique problems for modeling human diseases in mice. (Circ Res. 2007;101:523-531.)Key Words: elastin Ⅲ supravalvular aortic stenosis Ⅲ vascular disease Ⅲ transgenic mice M utations within the elastin gene lead to several elastinopathies in humans that affect large blood vessels, the skin, and the lung. For example, loss-of-function mutations that produce haploinsufficiency have been linked to supravalvular aortic stenosis (SVAS-MIM185500), a congenital narrowing of the ascending aorta and other vessels. SVAS can occur sporadically or as a familial condition with autosomaldominant inheritance. 1 More than 50 different mutations have been described that lead to isolated SVAS. [2][3][4][5][6][7] SVAS is also a component of Williams-Beuren syndrome (WBS-MIM194050), 3,8 a frequent heterozygous deletion of a Ϸ1.6 Mb segment at chromosome 7q11.23 that includes the elastin gene. 3 In contrast to the loss-of-function mutations typical of SVAS, evidence suggests that autosomal dominant cutis laxa (ADCL-MIM123700) occurs through a dominant-negative mechanism. ADCL is characterized by lax skin with other internal organ involvement. Most elastin mutations associated with this disease are single nucleotide deletions near the 3Ј end of the gene 9 -11 resulting in missense sequence that alters the character of a biologically important domain at the end of the tropoelastin molecule. 12 ELN has also been suggested to be a susceptibility gene for hypertension, 13 emphysema, 14 and intracranial aneurysms. 15 ELN encodes a protein made up of alternating hydrophobic and crosslinking domains. 16 This repeating arrangement reflects the exon structure of the gene, with each type of domain encoded by distinct exon...

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Elastin is an essential component of vertebrate arteries that provides elasticity and stores energy during the cardiac cycle. Elastin production in the arterial wall begins midgestation but increases rapidly during the last third of human and mouse development, just as blood pressure and cardiac output increase sharply. The aim of this study is to characterize the structure, hemodynamics, and mechanics of developing arteries with reduced elastin levels and determine the critical time period where elastin is required in the vertebrate cardiovascular system. Mice that lack elastin (Eln(-/-)) or have approximately one-half the normal level (Eln(+/-)) show relatively normal cardiovascular development up to embryonic day (E) 18 as assessed by arterial morphology, left ventricular blood pressure, and cardiac function. Previous work showed that just a few days later, at birth, Eln(-/-) mice die with high blood pressure and tortuous, stenotic arteries. During this period from E18 to birth, Eln(+/-) mice add extra layers of smooth muscle cells to the vessel wall and have a mean blood pressure 25% higher than wild-type animals. These findings demonstrate that elastin is only necessary for normal cardiovascular structure and function in mice starting in the last few days of fetal development. The large increases in blood pressure during this period may push hemodynamic forces over a critical threshold where elastin becomes required for cardiovascular function. Understanding the interplay between elastin amounts and hemodynamic forces in developing vessels will help design treatments for human elastinopathies and optimize protocols for tissue engineering.

Background: A humanized mouse was developed to study elastin assembly and the pathogenesis of cutis laxa. Results: Mutant transcripts incorporate into elastic fibers of skin and lung with adverse effects but not aorta. Conclusion: Elastin frameshift mutations alter elastin assembly domains. Significance: The mechanism of elastic fiber assembly may not be the same in all tissues.

Background: Variability in vascular pathology is associated with elastin loss-of-function mutations. Results: Quantitative trait loci and several candidate genes that modify vessel pathology were identified in a mouse model of elastin insufficiency. Conclusion: The effects of elastin insufficiency are determined by interactions between the primary elastin defect and unrelated secondary modifiers. Significance: Identification of modifier genes enhances our understanding of disease mechanisms associated with elastin mutations.