title: The pathogenesis of Alport syndrome involves type IV collagen molecules containing the alpha 3(IV) chain: evidence from anti-GBM nephritis after renal transplantation.
abstract: Mutations in the COL4A5 collagen gene have been implicated as the primary defect in Alport syndrome, a heritable disorder characterized by sensorineural deafness and glomerulonephritis that progresses to end-stage renal failure. In the present study, the molecular nature of the defect in Alport glomerular basement membrane (GBM) was explored using anti-GBM alloantibodies (tissue-bound and circulating) produced in three Alport patients subsequent to renal transplantation. The alloantibodies bound to the alpha 3(IV)NC1 domain of type IV collagen and not to any other basement membrane component. In tissue sections, the alloantibodies bound specifically to peripheral GBM in normal kidney and the affected renal transplant but not to that of Alport kidney. These results establish that: the alpha 3 chain in type IV collagen molecules, the Goodpasture autoantigen, is the target alloantigen in post-transplant anti-GBM nephritis in patients with Alport syndrome, and that a molecular commonality exists in the pathogenesis of anti-GBM nephritis causing loss of renal allografts in patients with Alport syndrome and renal failure in patients with Goodpasture syndrome. These findings implicate: (1) defective assembly of type IV collagen molecules containing the alpha 3(IV) chain in Alport GBM; and (2) the existence of a mechanism linking the assembly of molecules containing the alpha 3(IV) chain with those containing the alpha 5(IV) chain.
authors.affiliation: Department of Biochemistry/Molecular Biology, University of Kansas Medical Center, Kansas City.
authors.forename: B G
authors.initials: BG
authors.lastname: Hudson
authors.forename: R
authors.initials: R
authors.lastname: Kalluri
authors.forename: S
authors.initials: S
authors.lastname: Gunwar
authors.forename: M
authors.initials: M
authors.lastname: Weber
authors.forename: F
authors.initials: F
authors.lastname: Ballester
authors.forename: J K
authors.initials: JK
authors.lastname: Hudson
authors.forename: M E
authors.initials: ME
authors.lastname: Noelken
authors.forename: M
authors.initials: M
authors.lastname: Sarras
authors.forename: W R
authors.initials: WR
authors.lastname: Richardson
authors.forename: J
authors.initials: J
authors.lastname: Saus
mesh_terms: D000328:Adult; D001324:Autoantigens; D001485:Basement Membrane / Q000276:immunology; D003094:Collagen / Q000235:genetics*; D024141:Collagen Type IV; D006801:Humans; D007518:Isoantibodies / Q000096:biosynthesis; D007519:Isoantigens; D007678:Kidney Glomerulus / Q000276:immunology; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D009393:Nephritis / Q000209:etiology* / Q000276:immunology; D009394:Nephritis, Hereditary / Q000209:etiology* / Q000235:genetics / Q000276:immunology
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D007518:Isoantibodies; D007519:Isoantigens; C057112:type IV collagen alpha3 chain; D003094:Collagen