Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

Abstract

asement membranes form a complex surface on which epithe-lial cells reside. These membranes provide morphogenic cues that determine the fate of cells, the polarization of subcellular constituents, and the location of cell receptors and transporters. 1-3 Basement membranes are assembled through an in-terweaving of type IV collagen (collagen IV) with laminins, nidogen, and sulfated prote-oglycans. 4,5 Collagen IV belongs to a family of collagenous proteins that has at least 25 distinct members. The COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6 genes 6-13 encoding the six chains of collagen IV — a 1(IV) through a 6(IV) — are selec-tively expressed in different membranes at various stages of embryonic development. 14 This selectivity accounts for the location of disease and the clinical consequences of in-jury to collagen IV. Damage to collagen IV due to mutation (in Alport's syndrome) or an immune attack (in Goodpasture's syndrome) disrupts the function of attached epithe-lia and leads to organ impairment. In 1927, Alport reported that deafness was a feature of a previously described fa-milial nephropathy that caused uremia in males but spared females. 15 Splitting of the glomerular basement membrane, hematuria, interstitial nephritis, and progressive kid-ney failure explain the renal aspects of the disorder. 16 The cause of Alport's syndrome was unknown 17 until mutations were discovered in the COL4A3, COL4A4, and COL4A5 collagen genes. 18-20 Some carriers of a mutant collagen IV gene are thought to have a variant of Alport's syndrome termed benign familial hematuria or thin glomerular base-ment membrane disease. 18,21-24 In 1958, Stanton and Tange 25 described nine patients with a pulmonary–renal disor-der they called Goodpasture's syndrome after an earlier report by Ernest Goodpas-ture. 26 The classic presentation of Goodpasture's syndrome is explosive lung hem-orrhage with nephritis that is often crescentic; the syndrome is rapidly fatal if left untreated. 27,28 It is an immune disorder with serum antibodies directed against par-ticular regions of the a 3(IV) chain of collagen IV in lung and kidney. 29-33 For many years, a connection between the two syndromes was suspected, because most glomeruli from the kidneys of patients with Alport's syndrome do not stain by the immunofluorescent method with antibodies from patients with Goodpasture's syndrome. 34 This curiosity focused attention on collagen IV, and today we know that the pathogenesis of both diseases is linked to the same a 3. a 4. a 5(IV) collagen pro-tomer. 14,35-37 Collagen IV was first isolated by Kefalides from glomerular basement membrane in 1966, 38 and during the past 35 years, the structures of the six chains that assemble into collagen IV molecules have been elucidated by numerous investigators. 4,6-14,39-44 Each