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, Benjamin A. Raby

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)355-362
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume33
Issue number4
DOIs
StatePublished - Oct 2005

Keywords

  • Chronic obstructive pulmonary disease
  • Elastin
  • Extracellular matrix
  • Genetics
  • Mutation

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    Kelleher, C. M., Silverman, E. K., Broekelmann, T., Litonjua, A. A., Hernandez, M., Sylvia, J. S., Stoler, J., Reilly, J. J., Chapman, H. A., Speizer, F. E., Weiss, S. T., Mecham, R. P., & Raby, B. A. (2005). A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease. American Journal of Respiratory Cell and Molecular Biology, 33(4), 355-362. https://doi.org/10.1165/rcmb.2005-0206OC