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Published ahead of print on August 4, 2005, doi:10.1165/rcmb.2005-0206OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 4, October 2005, 355-362

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Submitted on June 1, 2005
Revised on August 3, 2005

A Functional Mutation in the Terminal Exon of Elastin in Severe, Early Onset COPD

Cassandra M Kelleher1, Edwin K Silverman2*, Thomas Broekelmann1, Augusto A Litonjua2, Melvin Hernandez3, Jody Senter Sylvia3, Joan Stoler4, John J Reilly5, Harold A Chapman6, Frank E Speizer7, Scott T Weiss7, Robert P Mecham1, and Benjamin A Raby8

1 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA, 2 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 3 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA, 4 Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA, 5 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 6 Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA, 7 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA, 8 Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

* To whom correspondence should be addressed. 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.




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