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Published ahead of print on August 4, 2005, doi:10.1165/rcmb.2005-0206OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 33, pp. 355-362, 2005
© 2005 American Thoracic Society
DOI: 10.1165/rcmb.2005-0206OC

A Functional Mutation in the Terminal Exon of Elastin in Severe, Early-Onset Chronic Obstructive Pulmonary Disease

Cassandra M. Kelleher, Edwin K. Silverman, Thomas Broekelmann, Augusto A. Litonjua, Melvin Hernandez, Jody S. Sylvia, Joan Stoler, John J. Reilly, Harold A. Chapman, Frank E. Speizer, Scott T. Weiss, Robert P. Mecham and Benjamin A. Raby

Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; Channing Laboratory, and Division of Pulmonary and Critical Medicine, Department of Medicine, Brigham and Women's Hospital; Harvard Medical School; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center; Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts; and Division of Pulmonary and Critical Medicine, Department of Medicine, University of California San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Edwin K. Silverman, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115. E-mail: ed.silverman{at}channing.harvard.edu

We describe a novel variant in the terminal exon of human elastin, c.2318 G>A, resulting in an amino acid substitution of glycine 773 to aspartate (G773D) in a pedigree with severe early-onset chronic obstructive pulmonary disease (COPD). Transfection studies with elastin cDNAs demonstrate that the glycine to aspartate change compromises the ability of the mutant protein to undergo normal elastin assembly. Other functional consequences of this amino acid substitution include altered proteolytic susceptibility of the C-terminal region of elastin and reduced interaction of the exon 36 sequence with matrix receptors on cells. These results suggest that the G773D variant confers structural and functional consequences relevant to the pathogenesis of COPD.

Key Words: chronic obstructive pulmonary disease • elastin • extracellular matrix • genetics • mutation




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