title: Patients with Goodpasture's disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen alpha 3 chain.
abstract: BACKGROUND
  Goodpasture's disease (GP) is a rare but severe disease characterized by anti-glomerular basement membrane antibodies, rapidly progressive glomerulonephritis and lung haemorrhage. The autoantibodies are restricted to a narrow epitope region on the NC1 domain of the alpha 3 chain of type IV collagen. GP is strongly associated with major histocompatibility complex (MHC) allele HLA DRB1-15. Recent research, however, has failed to identify a T-cell epitope with molecular characteristics that explain the relationship between the MHC class II molecule and the autoantibody generation. We hypothesized that an as yet unidentified sequence variant in exons 48-52 of the COL4A3 gene that encodes the NC1 domain of the type IV collagen alpha 3 chain could generate a new peptide sequence that, through interaction with specific MHC class II molecules, would increase the risk of developing GP.
  
  
  METHODS
  All patients previously treated for GP at the Lund and Malmö University Hospitals, who were alive at the time of the study, were asked to participate. DNA was extracted from leukocytes and subjected to genomic tissue typing and sequencing of the COL4A3 gene exons 48-52.
  
  
  RESULTS
  All 15 patients in the study had a nucleotide sequence in the COL4A3 gene encoding a protein identical to GenBank entry NM_000091. HLA D allele distribution was in line with previous publications, showing a strong positive association between HLA DRB1-15, HLA DQB1-6 and GP (P<0.02). Of the 15 GP patients, 73% carried HLA DRB1-15 and 87% carried the HLA DQB1-6 antigen. Corresponding figures for the controls were 27 and 50%.
  
  
  CONCLUSIONS
  This study effectively falsifies the hypothesis that a minor alteration in the COL4A3 gene could be a major factor in the aetiology of GP. Scandinavian GP patients have an MHC distribution similar to that which has been described previously for Anglo-Saxon patients.
authors.affiliation: Department of Nephrology, Lund University, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Persson
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Hertz
authors.forename: Malin
authors.initials: M
authors.lastname: Carlsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Hellmark
authors.forename: Inger
authors.initials: I
authors.lastname: Juncker
authors.forename: Jörgen
authors.initials: J
authors.lastname: Wieslander
authors.forename: Mårten
authors.initials: M
authors.lastname: Segelmark
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019867:Anti-Glomerular Basement Membrane Disease / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D001324:Autoantigens / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics*; D005260:Female; D006681:HLA-D Antigens; D006801:Humans; D008297:Male; D008875:Middle Aged; D017434:Protein Structure, Tertiary / Q000235:genetics; D017422:Sequence Analysis, DNA; D016036:Seroepidemiologic Studies; D013548:Sweden / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D006681:HLA-D Antigens; C057112:type IV collagen alpha3 chain