Characterization and expression of multiple alternatively spliced transcripts of the Goodpasture antigen gene region. Goodpasture antibodies recognize recombinant proteins representing the autoantigen and one of its alternative forms.
Collagen IV, the major component of basement membranes, is composed of six distinct alpha chains (alpha 1-alpha 6). Atypically among the collagen IV genes, the exons encoding the carboxyl-terminal region of the human alpha 3(IV) chain undergo alternative splicing. This region has been designated as the Goodpasture antigen because of its reactivity in the kidney and lung with the pathogenic autoantibodies causing Goodpasture syndrome. The data presented in this report demonstrate that, in human kidney, the gene region encompassing the Goodpasture antigen generates at least six alternatively spliced transcripts predicting five distinct proteins that differ in their carboxyl-terminus and retain, except in one case, the exon that harbors the characteristic amino-terminus of the antigen. Goodpasture antibodies specifically recognize recombinant proteins representing the antigen and the alternative form that retains the amino-half of the antigen, suggesting that this moiety could be involved in the in vivo binding of the pathogenic antibodies. Furthermore, the sera of control individuals contain autoantibodies against the antigen that can be differentiated from those causing the syndrome based on their specific reactivities, suggesting that the binding of the pathogenic autoantibodies to a specific determinant likely trigger a distinct and unique cascade of events causing the disease.
Penadés
J R
JR
Fundación Valenciana de Investigaciones Biomédicas, Instituto de Investigaciones Citológicas, València, Spain.
Bernal
D
D
Revert
F
F
Johansson
C
C
Fresquet
V J
VJ
Cervera
J
J
Wieslander
J
J
Quinones
S
S
Saus
J
J
D017398:Alternative Splicing / Q000235:genetics* / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D003094:Collagen / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D024141:Collagen Type IV; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000276:immunology; D014158:Transcription, Genetic
D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D017931:DNA Primers; D012333:RNA, Messenger; D011994:Recombinant Proteins; C057112:type IV collagen alpha3 chain; D003094:Collagen