A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease.

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.

• Authors: 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
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 33 Issue 4 Pg. 355-62 (Oct 2005) ISSN: 1044-1549 [Print] United States
• PMID: 16081882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Tropoelastin
• Elastin

Topics

• Alternative Splicing
• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Cattle
• Cell Adhesion
• Cells, Cultured
• DNA Mutational Analysis
• Elastin (genetics, metabolism)
• Exons
• Female
• Humans
• Male
• Middle Aged
• Molecular Sequence Data
• Multicenter Studies as Topic
• Pedigree
• Polymorphism, Genetic
• Pulmonary Disease, Chronic Obstructive (genetics, physiopathology)
• Randomized Controlled Trials as Topic
• Tropoelastin (metabolism)