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(Circulation Research. 2007;101:523.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Functional Rescue of Elastin Insufficiency in Mice by the Human Elastin Gene

Implications for Mouse Models of Human Disease

Eiichi Hirano, Russell H. Knutsen, Hideki Sugitani, Christopher H. Ciliberto, Robert P. Mecham

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Mo.

Correspondence to Dr Robert Mecham, Washington University School of Medicine, Department of Cell Biology and Physiology, Campus Box 8228, 660 South Euclid Ave, St. Louis, MO 63110. E-mail bmecham{at}wustl.edu

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.

Key Words: elastin • supravalvular aortic stenosis • vascular disease • transgenic mice

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