A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease.
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.
Kelleher
Cassandra M
CM
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Silverman
Edwin K
EK
Broekelmann
Thomas
T
Litonjua
Augusto A
AA
Hernandez
Melvin
M
Sylvia
Jody S
JS
Stoler
Joan
J
Reilly
John J
JJ
Chapman
Harold A
HA
Speizer
Frank E
FE
Weiss
Scott T
ST
Mecham
Robert P
RP
Raby
Benjamin A
BA
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
D014333:Tropoelastin; D004549:Elastin