The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family.

The glomerular basement membrane (GBM), a principal component of the filtration barrier, is abnormal in several renal diseases. Notable examples include Alport syndrome, Goodpasture (GP) syndrome, and diabetic nephropathy. This commonality, as defined by previous clinical and basic studies, has provided the impetus to explore the chemistry and biology of the GBM as a basis for discovery of pathogenic mechanisms underlying these and other kidney diseases. Years of intensive investigations have culminated in the discovery of a collagen IV family of six -chains and its role in renal diseases. These -chains form complex networks in basement membranes that underlie epithelia in all metazoan. The networks are essential for tissue function, providing structural support and serving as ligands for cell receptors. We now know that one of these networks in the GBM is the target for autoantibodies in GP syndrome, and this same network is profoundly disrupted by genetic mutations in patients with Alport syndrome. A cornerstone of these discoveries was the use of “plasma autoantibodies” from patients with GP syndrome as molecular probes for the search of target antigens in GBM and the clinical observation of a “molecular commonality” in the GBM of patients with GP syndrome and Alport syndrome. These advances were presented from a clinical perspective in a previous review (1). In this article, I focus on the highlights of nearly four decades of intellectual paths taken by numerous investigators from many countries, including me and my co-workers, that have led to the discovery of the collagen IV family and its role in renal diseases. The paths were blazed by crafting a successive series of simple and direct questions about the relationships between molecular structure and disease. Also, I present the major concepts that have emerged from these efforts about the molecular architecture of the collagen IV network and its molecular defects that underlie several diseases that affect the GBM. A key discovery is the novel 3. 4. 5 network of collagen IV and its central role in the pathogenesis of both GP and Alport syndromes. An important feature of this journey of discovery was the comparative analysis of different tissues from different animal species—a hallmark of the exploratory philosophy of Dr. Homer Smith. I am most grateful and honored to receive the 2003 Homer Smith Award from the American Society of Nephrology.