title: 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.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Cassandra M
authors.initials: CM
authors.lastname: Kelleher
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Thomas
authors.initials: T
authors.lastname: Broekelmann
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Melvin
authors.initials: M
authors.lastname: Hernandez
authors.forename: Jody S
authors.initials: JS
authors.lastname: Sylvia
authors.forename: Joan
authors.initials: J
authors.lastname: Stoler
authors.forename: John J
authors.initials: JJ
authors.lastname: Reilly
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
authors.forename: Frank E
authors.initials: FE
authors.lastname: Speizer
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004549:Elastin / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015337:Multicenter Studies as Topic; D010375:Pedigree; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D014333:Tropoelastin / Q000378:metabolism
chemical_list: D014333:Tropoelastin; D004549:Elastin