Journal of the American Society of Nephrology
2008 JASN IMPACT FACTOR 7.505 HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP 
    advanced
CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION


J Am Soc Nephrol 15: 2514-2527, 2004
© 2004 American Society of Nephrology
doi: 10.1097/01.ASN.0000141462.00630.76
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hudson, B. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hudson, B. G.

HOMER W. SMITH AWARD LECTURE

The Molecular Basis of Goodpasture and Alport Syndromes: Beacons for the Discovery of the Collagen IV Family

Billy G. Hudson

Departments of Medicine and Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee

Correspondence to Dr. Billy G. Hudson, Departments of Medicine and Biochemistry, Vanderbilt University School of Medicine, B-3102 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2372. Phone: 615-322-7298; Fax: 615-322-7381; E-mail: billy.hudson{at}vanderbilt.edu

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 {alpha}-chains and its role in renal diseases. These {alpha}-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 {alpha}3.{alpha}4.{alpha}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.

GBM in Disease

The GBM is positioned between the endothelial and epithelial cell layers of the glomerular capillary wall (Figure 1). It is a specialized form of extracellular matrix of ~300 to 350 nm in thickness that provides mechanical support, and its components serve as ligands for receptors that influence cell behavior. Another key role of the GBM is ultrafiltration of circulating blood, blocking the passage of cellular components and large proteins from entering the urinary space.



View larger version (82K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 1. Schematic illustration of human glomerulus in health and disease. Cross-section of a normal human glomerulus shows the three layers of the filtration barrier: the fenestrated endothelium, the glomerular basement membrane (GBM), and the podocyte slit diaphragm (SD) between the podocyte foot processes (FP). The filtration of blood occurs through these three layers with decreasing pore size and increasing selectivity. In thin basement membrane disease, the normal thickness of the GBM is decreased. The GBM in Alport kidney is characterized by irregular thinning and thickening, splitting, and multi-laminations, which lead to progressive renal failure. In Goodpasture (GP) syndrome, the GBM is targeted by autoantibodies, leading to an inflammatory response and loss of filtration function. Thickening of the GBM occurs in diabetic nephropathy, resulting in alteration of the normal structure and function of the GBM.

 
The GBM is affected in several renal diseases (Figure 1). The thickness of the GBM increases in patients with diabetic nephropathy, which together with expansion of the mesangium leads to progressive loss of glomerular filtration (2). Autoantibodies bind the GBM in patients with GP syndrome, which ignites an overwhelming inflammatory response that leads to the rapid loss of kidney function (3–7). Genetic mutations in Alport syndrome cause splitting and multi-laminations of the GBM, which leads to a slow progressive loss of renal function (8–13). Also, mutations underlie thin basement membrane disease, leading to hematuria (14–17). The commonality of abnormal GBM in these and several other glomerular diseases, as defined by numerous clinical investigations in the 1960s, focused the attention of my research group and other scientists on a quest to define the molecular structure of the GBM as a foundation for unraveling the molecular basis of these diseases.

Importantly, these clinical observations framed fundamental questions about the disease mechanisms. Among them were two simple and direct questions: (1) "What is the identity of the autoantigen of GBM in GP syndrome?" (2) "Which component of the GBM is mutated in Alport syndrome?" In answering these questions, a critical observation was made by several investigators in the early 1980s linking these two syndromes (18–21). In a classic paper, Curtis Wilson and colleagues (19) showed that plasma of patients with GP syndrome contained anti-GBM antibodies that would bind the GBM of normal kidney but did not react with the GBM of an Alport kidney (Figure 2). Moreover, anti-GBM antibodies that had developed in a renal transplant recipient with Alport syndrome reacted with the GBM of normal kidneys but not with the GBM of Alport kidney. This led them to conclude that the absent antigen in Alport syndrome is related to the nephritogenic antigen in GP syndrome. The concept of a "molecular commonality" between the two syndromes ultimately served as an intellectual cornerstone for the discovery of collagen IV as a family of six {alpha}-chains.



View larger version (51K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 2. Discovery of a "molecular commonality" in the GBM of patients with Alport and GP syndromes. Autoantibodies from patients with GP syndrome react with the GBM of a normal kidney but fail to react with the GBM of an Alport kidney. Also, anti-GBM alloantibodies, that had developed in a patient with Alport syndrome after receiving a renal allograft, reacted with the GBM of normal kidney but not with the GBM of Alport kidney. These findings indicated the lack of the GP autoantigen in the Alport kidney.

 
Discovery of Collagen IV and the {alpha}1 and {alpha}2 Chains

In the mid-1960s and early 70s, studies were focused on the isolation and biochemical characterization of GBM from a variety of animal species (22–29). The findings revealed that the amino acid composition of isolated GBM reflected relatedness with collagen, having a high content of glycine, hydroxyproline, and hydroxylysine. In 1966, Nicolas Kefalides (22) reported the first evidence for the existence of a collagen component in canine GBM, which he designated as collagen IV in a review article in 1973 (30). In the same year, Robert Spiro proposed that the GBM contains collagen-like polypeptides interrupted by noncollagenous sequences (31), a feature later confirmed by protein sequence analysis (32) and molecular cloning (33–36). Many investigators turned to basement membranes of other tissues and animal species to explore the nature of this collagen.

A soluble form of collagen IV was isolated by Rupert Timpl and co-workers (37) from the Engelbreth-Holm-Swarm tumor matrix from mouse tissue and shown to be a triple-helical protomer (Figure 3). The protomers were shown to self-assemble through end-to-end associations at their N-terminal (7S domain) to form tetramers and through their C-terminal noncollagenous domain (NC1) to form dimers (37,38). Later, the complete amino acid sequences of the constituent {alpha}1 and {alpha}2 chains (mouse and human) were determined by molecular cloning (33–36). We found this collagen also exists in the invertebrate Ascaris suum (39,40). Other investigators found the genes encoding these chains in Drosophila, C. elegans, and Hydra vulgaris (41–44), revealing >500 million years of evolutionary conservation of their structural features for self-association and network formation.



View larger version (70K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 3. Structure of collagen IV protomers and their assembly into networks. The protomer is composed of two {alpha}1 chains and one {alpha}2 chain and is characterized by a 7S triple helical domain at the N-terminal containing N-linked carbohydrate moieties, followed by a long triple helical collagenous domain and a noncollagenous NC1 trimer at the C-terminal. Interruptions in the Gly-Xaa-Yaa amino acid sequence at multiple sites along the collagenous domain confer flexibility, allowing for looping and supercoiling of protomers into networks, strengthen with interprotomer disulfide bonds. The protomer is "sugar coated" in which it contains a N-linked oligosaccharide unit on each chain at the 7S domain, and numerous disaccharide units (not shown) along the full-length collagenous domain (25, 118, 119). Once secreted into the extracellular matrix, collagen IV protomers form networks through dimerization at their C-terminal NC1 domains and through tetramer formation at their N-terminal 7S domains.

 
Recent advances in x-ray crystallography allowed us and others to answer a fundamental question about the network structure of the {alpha}1 and {alpha}2 chains: "What is the three-dimensional structure of the NC1 hexamer that connects protomers in the network?" (45,46). The x-ray structure of the {alpha}1.{alpha}2 hexamer has provided molecular insights into the structural basis of protomer and network assembly. In brief, it reveals the detailed interactions of all 20,300 atoms of the NC1 hexamer in which the NC1 monomers have a novel fold of {beta}-sheets interacting through a domain-swapping mechanism. As described below, these features provide insights into the pathogenic mechanisms underlying both GP and Alport syndromes (45–47).

Discovery of the {alpha}3 and {alpha}4 Chains and Identity of GP Autoantigen

As progress was being made by others on deciphering the molecular structure of collagen IV from the Engelbreth-Holm-Swarm tumor matrix, we focused our work to answer the question: "What is the molecular organization of the GBM collagen?" as a strategy to gain insights into GBM abnormalities. We used pepsin (48,49) and chemical extraction (50,51) to solubilize the components of GBM for biochemical analysis. Later, bacterial collagenase digestion of GBM was used to solubilize the NC1 domains of the known {alpha}1 and {alpha}2 chains of collagen IV. Upon excision from the GBM, these NC1 domains appeared as monomers and dimers with molecular masses of ~25 and 50 kD (Figure 4).



View larger version (37K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 4. Two independent lines of investigation led to the discovery of the {alpha}3 chain of collagen IV and its identity as the GP autoantigen. One line of investigation was on the chemical characterization of the collagenous component of GBM, and the other line was on the search for the molecular identity of the GP autoantigen. Both lines involved the use of collagenase to solubilize the components that yielded ~25-kD monomers and ~50-kD dimers. The similarity of these components first led to the identification of the GP antigen as the NC1 domains of the {alpha}1 and {alpha}2 chains of collagen IV (58,59). Subsequent studies to identify which chain carried the GP epitopes led to the discovery that the epitopes resided in the NC1 domain of a novel chain, designated as the {alpha}3 chain of collagen IV (62,64).

 
In an independent line of inquiry, others (52–57) sought to answer the question, "What is the molecular identity of the GP autoantigen of GBM?" They also used collagenase to digest GBM for solubilization of components, rendering them suitable for biochemical and immunochemical analyses (Figure 4). Two collagenase-resistant fragments of an 25-kD monomer and an 50-kD dimer were found to react with GP antibodies, but their molecular identities were unknown.

At a Gordon Conference in 1982, we presented our findings about collagen IV, as did Jorgen Wieslander and Per Bygren about GP autoantigen. The two presentations juxtaposed independent findings of two protein fragments, a monomer of 25 kD and a dimer of 50 kD, which in both cases were isolated by collagenase digestion of GBM. It was apparent to both teams that the GP autoantigen was possibly the NC1 domain of the {alpha}1.{alpha}2 collagen IV network. A collaboration was begun to investigate this hypothesis, which provided evidence that the GP antigen is localized to the NC1 domains of collagen IV (58,59). Moreover, these and our other (51) studies established the existence of the {alpha}1.{alpha}2 network in GBM.

The finding that the GP antigen was the NC1 domain posed another question: "Which chain, {alpha}1 or {alpha}2, carries the epitope(s) for GP autoantibodies?" The monomers and dimers from bovine GBM were heterogeneous, existing as a multiplicity of components, designated M1, M2*, and M3 and D1 and D2*. Of these, only M2* and D2* reacted with GP antibodies (60) as did the human M283+ monomer (61). To reduce the sample complexity, we investigated the NC1 monomers from lens capsule basement membrane because they displayed a simpler pattern than those of GBM. They were fractionated by chromatography (Figure 5A), and then the N-terminal sequences of M1 (a and b), M2*, and M3 were determined by the Edman degradation procedure (62). To our surprise, the N-terminal sequences of monomers M2*(18 residues) and M3 (17 residues) showed that they were derived from distinct protein species other than {alpha}1 and {alpha}2 NC1 monomers, while still having a collagenous origin; i.e., the triplets of Gly-Xaa-Yaa sequences (Figure 5B). On the basis of these differences in primary structures and additional differences in physical properties, we proposed that the M2* and M3 monomers were the NC1 domains derived from two novel chains, named the {alpha}3 and {alpha}4, respectively (62). The existence of four chains ({alpha}1, {alpha}2, {alpha}3, and {alpha}4) led us to propose the existence of at least two distinct protomers of collagen IV: one composed of the {alpha}1 and {alpha}2 chains and the other of the {alpha}3 and {alpha}4 chains or a combination of these chains (63).



View larger version (69K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 5. The first evidence for the existence of the {alpha}3 and {alpha}4 chains of collagen IV. In an attempt to answer the question, "Which chain, the {alpha}1 or {alpha}2, carries the epitope (s) for GP autoantibodies?" the monomers from bovine lens capsule basement membrane were fractionated by HPLC chromatography. The original figure from reference 62 is shown in A. The fractions noted as M1a and b, M2*, and M3 were analyzed by electrophoresis (inset) and by N-terminal amino acid sequence analyses. The sequences of these isolated components were compared (B). M1 and M1b corresponded to the known {alpha}1 and {alpha}2 NC1 domains, whereas M2* and M3 were distinctly different. The collagenous origins of the components were indicated by the repeat sequences (Gly-Xaa-Yaa) with glycine as the third residue. The M2* and M3 monomers were designated as NC1 domains derived from novel {alpha}3 and {alpha}4 chains of collagen IV and the {alpha}3 chain as the GP autoantigen (62, 64).

 
The concept of two novel chains was met with controversy. The short N-terminal sequence was considered by some as insufficient information in view of the known primary structure of the {alpha}1 and {alpha}2 chains of ~1400 residues (33–36). Additional studies by us provided further sequence information that brought the total number of known residues to 32 for the M2* and 30 for M3 (64,65). The information provided further evidence that M2* was derived from a novel {alpha}3 chain and its identity as the GP antigen (62). The existence of the bovine {alpha}3 chain was verified 4 yr later by Steve Reeders and co-workers (66). Using molecular cloning, they isolated a cDNA that contained the 32 residues of the M2* monomer (Figure 6) and that encoded 471 residues of the {alpha}3 chain. Later, fragments of the human {alpha}3 chain were cloned (67–69), and in 1994, the complete primary structure of the human {alpha}3 chain was determined (70) (Figure 6). Overall, these studies, together with our other study (71), unambiguously established the existence of the {alpha}3 chain and its identity as the GP autoantigen. Findings of a partial cDNA sequence encoding the bovine {alpha}4 chain (72) and a full-length cDNA clone encoding the human {alpha}4 chain (73) further verified the existence of the {alpha}4 chain.



View larger version (94K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 6. The amino acid sequence for the human {alpha}3 chain of collagen IV. The collagenous domain, characterized by repeat triplet sequence (Gly-Xaa-Yaa) with glycine as every third residue, is distinguished from that of the NC1 domain (red) (70). The key to the discovery of the {alpha}3 chain in human was the previous discovery of its corresponding chain in bovine, in which its homologous N-terminal sequence of 32 amino acids residues (shown in the solid box) were derived from bovine M2* monomer and shown to be GLXGKPGDTGPPAAGAVMRGFVFTRHSQTTAI (62,64,65). These residues were first used to clone the bovine {alpha}3 chain (66). The position of GP epitopes on human sequence, EA followed by EB, are indicated (dashed boxes).

 
Discovery of {alpha}5 and {alpha}6 Chains and Alport Mutations

The "molecular commonality" between GP and Alport syndromes, defined by earlier studies (Figure 2) and confirmed by other studies showing the absence of the 28-kD GP-autoantigen in the Alport GBM (74), provided the conceptual framework for the discovery of two additional chains. On the basis of our discovery of the putative {alpha}3 chain and its identity as the GP autoantigen, we proposed that protomers and networks that contain the {alpha}3 chain must be absent in Alport GBM (63); hence, we established the {alpha}3 chain as the prime candidate for mutations in Alport syndrome. Because the gene locus for Alport had been mapped to position Xq22 on the X-chromosome (Figure 7B), we hypothesized that the locus for the COL4A3 gene was at the same site (Figure 7C) (63). The defect in Alport syndrome could not be due to the COL4A1 and COL4A2 genes because they had been mapped to chromosome 13 (75,76) (Figure 7A).



View larger version (40K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 7. Chromosomal localization of the human genes encoding {alpha}1 to {alpha}6 chains of collagen IV and the path to discovery of {alpha}5 and {alpha}6 chains. (A) The COL4A1 and COL4A2 genes, encoding the {alpha}1 and {alpha}2 chains, were the first collagen IV genes to be discovered and their locus mapped to chromosome 13, where they were shown to have a head-to-head orientation. (B) The locus for the Alport gene was mapped to a site on the X-chromosome. (C) The Alport gene was proposed to code for the {alpha}3 chain on the basis of the "molecular commonality" between GP and Alport syndromes involving the {alpha}3 chain. (D) Contrary to this proposal, the COL4A5 gene encoding the {alpha}5 chain was mapped to this site on the X-chromosome, and it was shown to be mutated in patients with Alport syndrome. (E) Later, the COL4A3 and COL4A4 genes encoding the {alpha}3 and {alpha}4 chains were mapped to chromosome 2. The head-to-head orientation of the COL4A1 and COL4A2 genes and the COL4A3 and COL4A4 genes posed the question, "Does a COL4A6 gene exist on the X-chromosome to pair with the COL4A5 gene? (F) By positional cloning, the COL4A6 gene encoding the {alpha}6 chain was discovered.

 
In 1991, two research groups led by Karl Tryggvason (77) and Jeannie Myers (78) identified cDNA clone encoding a human chain that did not correspond to that of the 34 residues derived from bovine {alpha}3 chain. At that time, the only sequence available for the {alpha}3 chain of collagen IV was the 34-residue sequence of the bovine {alpha}3 chain. With the likelihood of the existence of the {alpha}3 and {alpha}4 chains, they designated this new chain as the {alpha}5 chain of collagen IV and mapped the COL4A5 gene to the Alport locus on the X chromosome (Figure 7D) (77,78). Mutations in the COL4A5 gene were subsequently discovered in a family with Alport syndrome, confirming the identity of the defective gene (79). Later, the COL4A3 and COL4A4 genes were identified and mapped to chromosome 2 (80) (Figure 7E). The head-to-head orientations of the COL4A1 and COL4A2 genes and the COL4A3 and COL4A4 genes posed the question, "Does a COL4A6 gene exist on the X-chromosome to pair with the COL4A5 gene?" (Figure 7E). Indeed, the COL4A6 gene encoding the {alpha}6 chain of collagen IV was later discovered by two independent groups headed by Steve Reeders and Yoshifumi Ninomiya (81–83). Thus, the six genes are distributed in pairs with a head-to-head organization about three chromosomes (Figure 7F). The complete exon-intron structure of all six genes in mouse and human revealed a common ancestor gene (84–90).

Triple-Helical and Network Organization of the {alpha}3-{alpha}6 Chains

The discovery that the {alpha}5 chain is mutated in Alport syndrome posed a key question: "How do mutations in the {alpha}5 chain cause the absence of the {alpha}3 chain in Alport GBM?" The answer emerged from our further investigations of the triple-helical and network organization of the collagen IV chains. The well-described organization of the {alpha}1 and {alpha}2 chains (Figure 3) served as the paradigm for further investigations. The experimental strategies included fragmentation of networks with pseudolysin to release truncated triple-helical molecules (91,92) and with collagenase (93) to release NC1 hexamers for characterization.

The random combinations of the six {alpha}-chains theoretically allow for 56 different protomers. Various combinations of protomers could further self-associate, forming a multiplicity of networks that differ with respect to which protomers are connected through end-to-end interactions. However, only three protomers have so far been discovered: the {alpha}1.{alpha}1.{alpha}2 by others (37) and the {alpha}3.{alpha}4.{alpha}5 and {alpha}5.{alpha}5.{alpha}6 by us (Figure 8) (47,94). These protomers form three distinct networks: the {alpha}1.{alpha}1.{alpha}2 network shown in Figure 3, the {alpha}3.{alpha}4.{alpha}5 network shown in Figure 9, and the {alpha}1.{alpha}2.{alpha}5.{alpha}6 network (94) (not shown).



View larger version (25K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 8. Triple helical organization of the type IV collagen family. Six genetically distinct {alpha}-chains are arranged into three triple helical protomers that differ in their chain composition. Each protomer has a 7S triple helical domain at the N-terminal; a long, triple helical, collagenous domain in the middle of the molecule; and a noncollagenous (NC1) trimer at the C-terminal. Interruptions in the Gly-Xaa-Yaa amino acid sequence at multiple sites along the collagenous domain (grey rings) confer flexibility, allowing for looping and supercoiling of protomers into networks. The selection of {alpha}-chains for association into trimeric protomers is governed by molecular recognition sequences encoded within the hypervariable regions of NC1 domains. Reprinted from reference 1, with permission.

 


View larger version (69K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 9. Supramolecular structure of the novel {alpha}3.{alpha}4.{alpha}5 network underlying the pathogenesis of GP and Alport syndromes. The {alpha}3.{alpha}4.{alpha}5 protomer forms a highly cross-linked network as a result of the high number of disulfide bridges between protomers (compare Figures 3 and 9). Interactions through the N-terminal 7S and C-terminal NC1 domains are indicated (white boxes). The position of GP epitopes (A and B) are indicated on {alpha}3 chain. Modified from reference 1, with permission.

 
Importantly, our discovery of the {alpha}3.{alpha}4.{alpha}5 network provided a molecular understanding of the linkage between GP syndrome and Alport syndrome that had been established from the clinical studies (Figure 2) (47,92). Thus, mutations in the {alpha}5 chain in Alport syndrome could either prevent the assembly of the {alpha}3.{alpha}4.{alpha}5 protomer or result in defective protomers that cannot self-assemble into a network or are prone to a rapid degradation. Consequently, because the Alport GBM lacks the {alpha}3.{alpha}4.{alpha}5 network, the GP antigen would be absent as well. The absence of this network in the Alport GBM also explained why sometimes a renal allograft loses its function; in this case, the immune system of the Alport patient recognizes the {alpha}3.{alpha}4.{alpha}5 network as foreign, which elicits alloantibodies against the {alpha}3 and {alpha}5 NC1 domains present in the allograft (95).

The existence of three networks posed a logical question: "What is the molecular recognition mechanism for assembly of a chain-specific network?" Our studies revealed that the specificity of both protomer and network assembly is governed by "molecular recognition sequences" encoded within the NC1 domains (96). Thus, the molecular functions of the NC1 domains in assembly are (1) the initial alignment and selection of chains for protomer assembly and (2) the connection and selection of protomers for network assembly. Our recent x-ray structure of the NC1 hexamer provided further insights into this mechanism (45), although the recognition code remains a mystery.

Pathogenesis of GP Syndrome and the Cryptic Epitopes

In 1958, Stanton and Tange (97) described nine patients with a pulmonary-renal disorder that they called Goodpasture syndrome after an earlier report in 1919 by Ernest Goodpasture (98). The classic presentation of GP syndrome is pulmonary hemorrhage associated with rapidly progressive glomerulonephritis; the syndrome is fatal if left untreated (7). The syndrome is very rare, with an annual incidence of ~1 or 2 cases per million in the United States. The landmark studies of Lerner and Dixon (6) revealed that the nephritis is mediated by autoantibodies that bind the GBM.

As described herein, the autoantibodies are now known to target the {alpha}3.{alpha}4.{alpha}5 network of GBM, as well as alveolar basement membrane (99), and they specifically target the NC1 domain of the {alpha}3 chain. This knowledge set up a series of key questions about antibody binding: "What is the epitope?" "Where is it located within the primary structure of the NC1 domain?" The major experimental challenge was the conformational nature of the epitope. We resolved this issue by using "gain-of-function" studies with chimeras made of the nonreactive NC1 domain of the {alpha}1 chain in which unique regions were replaced by the corresponding sequence of {alpha}3 chain. The findings revealed two conformational epitopes, designated EA and EB, encompassing residues 17 to 31 and 127 to 141 of the {alpha}3 NC1 domain (Figure 6) (100). Key residues of the EA epitope have been identified by mutation analysis (101,102).

In the NC1 hexamer configuration, wherein the {alpha}3 NC1 domain interacts with its neighboring {alpha}4 and {alpha}5 NC1 domains, we found that both epitopes are cryptic (103,104), being inaccessible for antibody binding unless exposed by dissociation of the hexamer (Figure 10). This posed two other questions: "What is the three-dimensional localization of the epitopes?" "What is the basis of their crypticity?" For the answer, we determined the quaternary structure of the {alpha}3.{alpha}4.{alpha}5 hexamer (47) and then modeled its three-dimensional structure based on the x-ray structure of the homologous {alpha}1.{alpha}1.{alpha}2 hexamer (45). The findings revealed that the EA and EB are located near the triple-helical junction, and they are partially sequestered by interactions with the neighboring {alpha}5 and {alpha}4 NC1 domains (Figure 11).



View larger version (99K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 10. The identity and the cryptic nature of the EA epitope of the GP antigen. The immunodominant EA epitope was localized to a site, residues 17 to 31 (TAIPSCPEGTVPLYS), near the junction of the N-terminus of the NC1 domain and the triple-helical domain of the {alpha}3 chain of collagen IV. The epitope is cryptic, being inaccessible to GP antibodies until the hexamer is dissociated. The location of this EA epitope and that of the EB epitope are shown on the three-dimensional structure of the NC1 hexamer in Figure 11.

 


View larger version (76K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 11. The atomic structure of the {alpha}3.{alpha}4.{alpha}5 NC1 hexamer. The atomic structure of the hexamer shows how two protomers interact end to end at their C-terminal NC1 domains to form a NC1 hexamer. The three NC1 monomers of each protomer interact to form a trimeric cap that, in turn, interacts with the trimeric cap from another protomer to form the hexamer. Each NC1 monomer has a novel three-dimensional fold of the polypeptide chain, characterized mainly by {beta}-sheets, shown by the ribbon diagrams (left). The sites for the EA and EB epitopes are shown on the space-filling model of the hexamer (right). The atomic structure was modeled on the crystal structure of the homologous {alpha}1.{alpha}1.{alpha}2 NC1 hexamer.

 
Because the epitopes are hidden within the hexamer (103,104), it is presumed that an environmental factor, such as hydrocarbons (105) or tobacco smoke (106), is required to expose the cryptic epitopes present in alveolar basement membrane to the immune system (Figure 12). Indeed, in an experimental animal model, we showed that injection of monomers or dimers of {alpha}3 NC1 domain with exposed epitope induced anti-GBM disease (107,108,117). Endogenous oxidants can also open this immunologically privileged site in the GBM (109,110). In contrast, the epitopes of the alloantibodies, produced in some renal transplant recipients with Alport syndrome, are fully accessible on the hexamer surface, reside on the NC1 domains of the {alpha}3 and {alpha}5 chains, and seem to be distinct from the EA and EB epitopes (95,110) (Figure 12). This difference in structure between the epitopes for Alport allo-antibodies and GP auto-antibodies may reflect crucial features of the mechanisms underlying the cause of autoimmune GP syndrome and, thus, warrant the crafting of questions for future explorations.



View larger version (46K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 12. GP autoantibodies and Alport alloantibodies target different epitopes of the {alpha}3.{alpha}4.{alpha}5(IV) NC1 hexamer. Anti-GBM antibodies derive from an antigen-specific T cell and B cell response (T+B). The epitopes for the GP autoantibodies are inaccessible to anti-GBM antibodies unless there is a dissociation of the hexamer, which may be caused by oxidative stress. These epitopes reside on the {alpha}3(IV) NC1 domain and are partially sequestered by the adjacent {alpha}5(IV) NC1 and {alpha}4(IV) NC1 domains. In contrast, the epitopes for the Alport alloantibodies are accessible on the hexamer surface and reside on the {alpha}3(IV), {alpha}4(IV), and {alpha}5(IV) NC1 domains. Modified from reference 1, with permission.

 
Pathogenesis of Alport Syndrome and the Developmental Switch of the {alpha}3.{alpha}4.{alpha}5 Network

In 1927, Arthur Cecil Alport reported that deafness was a feature of a previously described familial nephropathy that caused uremia in males but spared females (111). Splitting of the GBM, hematuria, interstitial nephritis, and progressive kidney failure explained the renal aspects of the disorder. With the discovery of a collagenous component in GBM in 1966, Spears postulated in 1972 that this collagen was defective in Alport syndrome (11). The cause of Alport syndrome remained unknown until mutations were discovered in 1990 by Tryggvason and colleagues (79) in the COL4A5 gene encoding the {alpha}5 chain of collagen IV. Today, >300 different mutations in this gene have been identified. Subsequent studies have revealed that there are three genetic forms of Alport syndrome, all arising from mutations in the COL4A3, COL4A4, and COL4A5 genes (1,16,112,113). Full expression of Alport syndrome requires a mutation in the single COL4A5 allele carried by males with X-linked disease, or mutations in both alleles of COL4A3 and COL4A4 genes in subjects of either gender with the autosomal recessive form (17). Heterozygous mutations in COL4A3 and COL4A4 genes underlie thin basement membrane nephropathy, causing mild abnormalities of renal function (14–17).

These mutations interfere with the assembly of the {alpha}3.{alpha}4.{alpha}5 network in the GBM. As a consequence, they arrest the normal developmental switch (Figure 13A) from the {alpha}1.{alpha}1.{alpha}2 network to the {alpha}3.{alpha}4.{alpha}5 network, causing the persistence (Figure 13B) of the former in the GBM (114). Animal studies reveal that the {alpha}3.{alpha}4.{alpha}5 network is not essential for the early development of the glomerulus but is crucial for the long-term function of the filtration barrier later in life (115,116). We found that the embryonic {alpha}1.{alpha}1.{alpha}2 network (Figure 3) is more susceptible to proteolysis than the more heavily cross-linked {alpha}3.{alpha}4.{alpha}5 network (Figure 9) (92,114). Thus, the absence of the latter network may lead to proteolysis, which may explain why the GBM of Alport patients thickens unevenly, splits, and ultimately deteriorates, leading to progressive renal failure.



View larger version (35K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 13. Distribution and switches of collagen IV networks in glomerular development. (A) During early embryonic development, the {alpha}1.{alpha}1.{alpha}2(IV) network is present at all stages. In the mature glomerulus, this network is a component of Bowman’s capsule, mesangial matrix, and GBM. In contrast, the {alpha}3.{alpha}4.{alpha}5(IV) and {alpha}5.{alpha}5.{alpha}6(IV) networks first appear at the early capillary-loop stage. They seem to replace (dotted line) most of the {alpha}1.{alpha}1.{alpha}2(IV) network within the GBM and Bowman’s capsule, respectively, and they persist in the mature glomerulus. (B) In the X-linked form of Alport syndrome, this developmental switch in networks is arrested because of mutations in the {alpha}5(IV) chain. These mutations result in the persistence of the {alpha}1.{alpha}1.{alpha}2(IV) network and the absence of the {alpha}3.{alpha}4.{alpha}5(IV) and {alpha}5.{alpha}5.{alpha}6(IV) networks. Modified from reference 1, with permission.

 
Summary and Perspectives

The journey to unravel the molecular basis of GBM diseases has led to the discovery of the collagen IV family of six {alpha}-chains. Initial studies of diabetic nephropathy eventually resulted in the discovery of the {alpha}1 and {alpha}2 chains and their network organization. This network is a principal component of basement membranes underlying epithelia of all metazoa, as an ancient scaffold preserved >500 million years of evolution.

Our studies to unravel the molecular basis of GP syndrome directly led to the discovery of the {alpha}3 chain, which, in turn, led to the discovery of the {alpha}4, {alpha}5, and {alpha}6 chains and the defining of collagen IV as a family of six {alpha}-chains ({alpha}1 to {alpha}6). The autoantibodies from patients with GP syndrome would prove to be the beacon for our discovery of the {alpha}3 and {alpha}4 chains. The recognition of a "molecular commonality" between GP and Alport syndromes involving the GP antigen would prove to be a beacon for the discovery of the {alpha}5 and {alpha}6 chains.

Subsequently, we determined the network organization of the six {alpha}-chains in the glomerulus and discovered that the {alpha}3, {alpha}4, and {alpha}5 chains occur together in a single protomer ({alpha}3.{alpha}4.{alpha}5 protomer), forming a novel {alpha}3.{alpha}4.{alpha}5 network (Figure 9). This network provided a definitive explanation for the "molecular commonality" between GP and Alport syndromes. Moreover, the discovery of the {alpha}3.{alpha}4.{alpha}5 protomer and its network unified the findings of numerous investigators regarding the pathogenic mechanisms underlying several GBM diseases, as summarized in Figure 14. The pathogenesis of GP syndrome and all three forms of Alport syndrome (X-linked and autosomal recessive and dominant) are linked to this protomer, as is the pathogenesis of thin basement membrane disease and antibody-mediated posttransplant nephritis in Alport syndrome. The very same protomer may be involved in the pathogenesis of diabetic nephropathy, because it is the principal component of normal GBM.



View larger version (28K):
[in this window]
[in a new window]
[as a PowerPoint slide]
  		Figure 14. A schematic view of the {alpha}3.{alpha}4.{alpha}5 protomer (the GP protomer) and its role in renal diseases. Genetic mutations in the {alpha}5 chain leads to the X-linked form of Alport syndrome. Mutations in either the {alpha}3 or the {alpha}4 chain leads to the autosomal recessive and autosomal dominant forms of Alport syndrome and thin basement membrane disease. In Alport posttransplant anti-GBM nephritis, the alloantibodies are targeted to the NC1 domains of the {alpha}3 and {alpha}5 chains. In GP syndrome, the autoantibodies are targeted to the NC1 domain of the {alpha}3 chain.

 
In a previous review, we proposed naming the {alpha}3.{alpha}4.{alpha}5 protomer the "Goodpasture protomer" (1). This name highlights the important role that the Goodpasture antibodies had in the discovery of this protomer and further relates the entire protomer to the pathogenesis of GP and Alport syndromes. The GP protomer now serves as a new beacon for crafting questions as the basis for discovery of fundamental mechanisms underlying autoimmunity, functions, and assembly of networks in health and disease. The answers will hopefully provide molecular insights that lead to new therapies for GP and Alport syndromes and diabetic nephropathy.
"Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of Nature by careful investigation of cases of rare forms of disease. For it has been found, in almost all things, that what they contain of useful or applicable is hardly perceived unless we are deprived of them, or they become deranged in some way."

— —William Harvey, London, April 24th 1657 (120).

Acknowledgments

My work has been supported by the National Institutes of Health, American Heart Association, and BioStratum, Inc. My studies have greatly benefited by the research environments at Oklahoma State University, the University of Kansas Medical Center, and Vanderbilt University Medical Center.

I am indebted to many talented students, fellows, and associates from 26 countries for contributions: Fernando Ballester, Jon F. Barr, Pablo A. Bejarano, Olga Bondar, A. Ashley Booth, Corina M. Borza, Dorin-Bogdan Borza, Ariel Boutaud, Gerard S. Brungardt, Ralph J. Butkowski, Jean-Pierre Cartailler, Sergei Chetyrkin, Peale Chuang, Selene Colon, Ray Crigger, Brian L. Cussimanio, Pat Dalrymple, Bill Dameron, Neonila Danylevych, Michelle David, Douglas C. Dean, Anjana Dey, Shelley J. Edwards, Eric Eskioglu, J. Wesley Fox, J. William Freytag, Shanthi Govindaraj, Froilan Granero, Sripad Gunwar, Billy Hudson, Jr., Heather Hudson, Mark D. Hudson, Chung-Ho Hung, Izu Iwueke, Maciej Jodlowski, Tesfamichael Z. Kahsai, Raghuram Kalluri, Merja Kataja, Raja G. Khalifah, Jamshid Khoshnoodi, Daniel Kim, Jan P.M. Langeveld, Anu Leinonen, Patrick Mc Kinney, Missy E. Mathis, Gloria Monfort, Joni D. Mott, Kai-Olaf Netzer, Guojun Nie, Mikio Ohno, Benigno D. Peczon, Vadim Pedchenko, Rajani Prasad, Mohamed Rafi, G. Kesava Reddy, Juan Saus, Judy Shih, Narindar Singh, Dudley K. Strickland, Charles Swartz, Joaquin Timoneda, Parvin Todd, Sam Tryggvason, Roberto Vanacore, Paul A. Voziyan, Timothy W. West, Jorgen Wieslander, Billie J. Wisdom, Marita Wolf, Shi Yan, and Alaattin Yildiz. I am particularly indebted to Parvin Todd, my research manager for 30 yr. I am grateful for the artwork of Larry P. Howell.

I am indebted to two patients for their inspirations: Linda Langley, a survivor of GP syndrome; and Doug Strickland; who has Alport syndrome. Linda provided a legacy of autoantibodies for the discovery of the {alpha}3 chain, and they are still in use today for other studies—20 yr after her illness.

I am indebted to several colleagues for their contributions: Jared Grantham and Arnold Chonko for linking their patients, Linda Langley and Doug Strickland, to my research; and Kurt E. Ebner, Vince Gattone, Richard Kitching, Eric G. Neilson, Yoshifumi Ninomiya, Milton E. Noelken, Ambra Pozzi, Yoshikazu Sado, Michael P. Sarras, Munirathinam Sundaramoorthy, Paul S. Thorner, and Roy Zent for their intellectual contributions.

I am indebted to several mentors for equipping me for the journey: Dr. Haskell Jones for introducing me to "the world of science"; Dr. Robert Barker for introducing me to "the power of crafting a simple and direct question as the basis for discovery," and mentoring me in "carbohydrate chemistry"; Dr. William Blatt for introducing me to "research on Amicon artificial membranes and protein chemistry"; and Dr. Robert G. Spiro for mentoring me in "the importance of rigor in experimentation" and in "glycoprotein chemistry" and introducing me to "glycoprotein chemistry and the topics of basement membranes and diabetic nephropathy."

I am indebted to my family for their love, encouragement, and support: my parents, Cecil E. and Gladys B. Hudson; my children, Billy G. Hudson, Jr., Mark D. Hudson, and Heather Hudson; my sister, Ann Kincl; my brother, Johnny K. Hudson; and my wife, Dr. Julie K. Hudson.

References

  1. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG: Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 348: 2543–2556, 2003[Free Full Text]
  2. Drummond K, Mauer M: The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 51: 1580–1587, 2002[Abstract/Free Full Text]
  3. Steblay RW: Glomerulonephritis induced in sheep by injections of heterologous glomerular basement membrane and Freund’s complete adjuvant. J Exp Med 116: 253–271, 1962[Abstract]
  4. Lerner RA, Dixon FJ: Transfer of ovine experimental allergic glomerulonephritis (EAG) with serum. J Exp Med 124: 431–442, 1966[Abstract]
  5. Scheer RL, Grossman MA: Immune aspects of glomerulonephritis associated with pulmonary hemorrhage. Ann Intern Med 60: 1009, 1964[Abstract/Free Full Text]
  6. Lerner RA, Glassock RJ, Dixon FJ: The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 126: 989–1004, 1967[Abstract]
  7. Wilson CB, Borza DB, Hudson BG: Autoimmune renal disease involving renal basement membrane antigen. In: The Molecular Pathology of Autoimmune Diseases, edited by Theofilopoulos AN, Bona AC, Newark, Gordon & Breach Science Publishers/Harwood Academic Publishers, 2002, pp 981–1010
  8. Williamson DAJ: Alport’s syndrome of hereditary nephritis with deafness. Lancet 2: 1321–1323, 1961
  9. Hinglais N, Grunfeld JP, Bois E: Characteristic ultrastructural lesion of the glomerular basement membrane in progressive hereditary nephritis (Alport’s syndrome). Lab Invest 27: 473–487, 1972[Medline]
  10. Rumpelt HJ: Hereditary nephropathy (Alport syndrome): Correlation of clinical data with glomerular basement membrane alterations. Clin Nephrol 13: 203–207, 1980[Medline]
  11. Spear GS, Slusser RJ: Alport’s syndrome. Emphasizing electron microscopic studies of the glomerulus. Am J Pathol 69: 213–224, 1972[Medline]
  12. Yoshikawa N, Cameron AH, White RH: The glomerular basal lamina in hereditary nephritis. J Pathol 135: 199–209, 1981[CrossRef][Medline]
  13. Spear GS: Pathology of the kidney in Alport’s syndrome. Pathol Annu 9: 93–138, 1974[Medline]
  14. Badenas C, Praga M, Tazon B, Heidet L, Arrondel C, Armengol A, Andres A, Morales E, Camacho JA, Lens X, Davila S, Mila M, Antignac C, Darnell A, Torra R: Mutations in theCOL4A4 and COL4A3 genes cause familial benign hematuria. J Am Soc Nephrol 13: 1248–1254, 2002[Abstract/Free Full Text]
  15. Gross O, Netzer KO, Lambrecht R, Seibold S, Weber M: Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome. Nephrol Dial Transplant 18: 1122–1127, 2003[Abstract/Free Full Text]
  16. Longo I, Porcedda P, Mari F, Giachino D, Meloni I, Deplano C, Brusco A, Bosio M, Massella L, Lavoratti G, Roccatello D, Frasca G, Mazzucco G, Muda AO, Conti M, Fasciolo F, Arrondel C, Heidet L, Renieri A, De Marchi M: COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61: 1947–1956, 2002[CrossRef][Medline]
  17. Kashtan CE: Familial hematuria due to type IV collagen mutations: Alport syndrome and thin basement membrane nephropathy. Curr Opin Pediatr 16: 177–181, 2004[CrossRef][Medline]
  18. Olson DL, Anand SK, Landing BH, Heuser E, Grushkin CM, Lieberman E: Diagnosis of hereditary nephritis by failure of glomeruli to bind anti-glomerular basement membrane antibodies. J Pediatr 96: 697–699, 1980[CrossRef][Medline]
  19. McCoy RC, Johnson HK, Stone WJ, Wilson CB: Absence of nephritogenic GBM antigen(s) in some patients with hereditary nephritis. Kidney Int 21: 642–652, 1982[Medline]
  20. Jeraj K, Kim Y, Vernier RL, Fish AJ, Michael AF: Absence of Goodpasture’s antigen in male patients with familial nephritis. Am J Kidney Dis 2: 626–629, 1983[Medline]
  21. Kashtan C, Fish AJ, Kleppel M, Yoshioka K, Michael AF: Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis. J Clin Invest 78: 1035–1044, 1986
  22. Kefalides NA: A collagen of unusual composition and a glycoprotein isolated from canine glomerular basement membrane. Biochem Biophys Res Commun 22: 26–32, 1966[CrossRef][Medline]
  23. Spiro RG: Studies on the renal glomerular basement membrane. Preparation and chemical composition. J Biol Chem 242: 1915–1922, 1967[Abstract/Free Full Text]
  24. Spiro RG: Studies on the renal glomerular basement membrane. Nature of the carbohydrate units and their attachment to the peptide portion. J Biol Chem 242: 1923–1932, 1967[Abstract/Free Full Text]
  25. Spiro RG: The structure of the disaccharide unit of the renal glomerular basement membrane. J Biol Chem 242: 4813–4823, 1967[Abstract/Free Full Text]
  26. Westberg NG, Michael AF: Human glomerular basement membrane. Preparation and composition. Biochemistry 9: 3837–3846, 1970[CrossRef][Medline]
  27. Kefalides NA: Isolation and characterization of the collagen from glomerular basement membrane. Biochemistry 7: 3103–3112, 1968[CrossRef][Medline]
  28. Hudson BG, Spiro RG: Fractionation of glycoprotein components of the reduced alkylated renal glomerular basement membrane. J Biol Chem 247: 4239–4247, 1972[Abstract/Free Full Text]
  29. Hudson BG, Spiro RG: Studies on the native and reduced alkylated renal glomerular basement membrane. Solubility, subunit size, and reaction with cyanogen bromide. J Biol Chem 247: 4229–4238, 1972[Abstract/Free Full Text]
  30. Kefalides NA: Structure and biosynthesis of basement membranes. Int Rev Connect Tissue Res 6: 63–104, 1973[Medline]
  31. Spiro RG: Biochemistry of the renal glomerular basement membrane and its alterations in diabetes mellitus. N Engl J Med 288: 1337–1342, 1973
  32. Schuppan D, Timpl R, Glanville RW: Discontinuities in the triple helical sequence Gly-X-Y of basement membrane (type IV) collagen. FEBS Lett 115: 297–300, 1980[CrossRef][Medline]
  33. Soininen R, Haka-Risku T, Prockop DJ, Tryggvason K: Complete primary structure of the alpha 1-chain of human basement membrane (type IV) collagen. FEBS Lett 225: 188–194, 1987[CrossRef][Medline]
  34. Hostikka SL, Tryggvason K: The complete primary structure of the alpha 2 chain of human type IV collagen and comparison with the alpha 1(IV) chain. J Biol Chem 263: 19488–19493, 1988[Abstract/Free Full Text]
  35. Kurkinen M, Condon MR, Blumberg B, Barlow DP, Quinones S, Saus J, Pihlajaniemi T: Extensive homology between the carboxyl-terminal peptides of mouse alpha 1(IV) and alpha 2(IV) collagen. J Biol Chem 262: 8496–8499, 1987[Abstract/Free Full Text]
  36. Saus J, Quinones S, MacKrell A, Blumberg B, Muthukumaran G, Pihlajaniemi T, Kurkinen M: The complete primary structure of mouse alpha 2(IV) collagen. Alignment with mouse alpha 1(IV) collagen. J Biol Chem 264: 6318–6324, 1989[Abstract/Free Full Text]
  37. Timpl R, Wiedemann H, van Delden V, Furthmayr H, Kuhn K: A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem 120: 203–211, 1981[Medline]
  38. Yurchenco PD, Furthmayr H: Self-assembly of basement membrane collagen. Biochemistry 23: 1839–1850, 1984[CrossRef][Medline]
  39. Hung CH, Ohno M, Freytag JW, Hudson BG: Intestinal basement membrane of Ascaris suum. Analysis of polypeptide components. J Biol Chem 252: 3995–4001, 1977[Free Full Text]
  40. Hung CH, Noelken ME, Hudson BG: Intestinal basement membrane of Ascaris suum. Physical properties of the collagenous domain. J Biol Chem 256: 3822–3826, 1981[Free Full Text]
  41. Blumberg B, MacKrell AJ, Fessler JH: Drosophila basement membrane procollagen alpha 1(IV). II. Complete cDNA sequence, genomic structure, and general implications for supramolecular assemblies. J Biol Chem 263: 18328–18337, 1988[Abstract/Free Full Text]
  42. Guo XD, Kramer JM: The two Caenorhabditis elegans basement membrane (type IV) collagen genes are located on separate chromosomes. J Biol Chem 264: 17574–17582, 1989[Abstract/Free Full Text]
  43. Sibley MH, Johnson JJ, Mello CC, Kramer JM: Genetic identification, sequence, and alternative splicing of the Caenorhabditis elegans alpha 2(IV) collagen gene. J Cell Biol 123: 255–264, 1993[Abstract/Free Full Text]
  44. Fowler SJ, Jose S, Zhang X, Deutzmann R, Sarras MP Jr, Boot-Handford RP: Characterization of hydra type IV collagen. Type IV collagen is essential for head regeneration and its expression is up-regulated upon exposure to glucose. J Biol Chem 275: 39589–39599, 2000[Abstract/Free Full Text]
  45. Sundaramoorthy M, Meiyappan M, Todd P, Hudson BG: Crystal structure of NC1 domains: Structural basis for type IV collagen assembly in basement membranes. J Biol Chem 277: 31142–31153, 2002[Abstract/Free Full Text]
  46. Than ME, Henrich S, Huber R, Ries A, Mann K, Kuhn K, Timpl R, Bourenkov GP, Bartunik HD, Bode W: The 1.9-A crystal structure of the noncollagenous (NC1) domain of human placenta collagen IV shows stabilization via a novel type of covalent Met-Lys cross-link. Proc Natl Acad Sci U S A 99: 6607–6612, 2002[Abstract/Free Full Text]
  47. Borza DB, Bondar O, Todd P, Sundaramoorthy M, Sado Y, Ninomiya Y, Hudson BG: Quaternary organization of the Goodpasture autoantigen, the {alpha}3(IV) collagen chain. Sequestration of two cryptic autoepitopes by intraprotomer interactions with the {alpha}4 and {alpha}5 NC1 domains. J Biol Chem 277: 40075–40083, 2002[Abstract/Free Full Text]
  48. West TW, Fox JW, Jodlowski M, Freytag JW, Hudson BG: Bovine glomerular basement membrane. Properties of the collagenous domain. J Biol Chem 255: 10451–10459, 1980[Free Full Text]
  49. Dean DC, Peczon BD, Noelken ME, Hudson BG: Bovine glomerular basement membrane. Characterization of an alpha-size collagenous polypeptide. J Biol Chem 256: 7543–7548, 1981[Abstract/Free Full Text]
  50. Fox JW, Butkowski RJ, Hudson BG: Detergent-prepared glomerular basement membrane is composed of a heterogeneous group of polypeptides. J Biol Chem 256: 9313–9315, 1981[Abstract/Free Full Text]
  51. Dean DC, Barr JF, Freytag JW, Hudson BG: Isolation of type IV procollagen-like polypeptides from glomerular basement membrane. Characterization of pro-alpha 1(IV). J Biol Chem 258: 590–596, 1983[Abstract/Free Full Text]
  52. McIntosh RM, Griswold W: Antigen identification in Goodpasture’s syndrome. Arch Pathol 92: 329–333, 1971[Medline]
  53. Mahieu PM, Lambert PH, Maghuin-Rogister GR: Primary structure of a small glycopeptide isolated from human glomerular basement membrane and carrying a major antigenic site. Eur J Biochem 40: 599–606, 1973[Medline]
  54. Marquardt H, Wilson CB, Dixon FJ: Isolation and immunological characterization of human glomerular basement membrane antigens. Kidney Int 3: 57–65, 1973[Medline]
  55. Holdsworth SR, Golbus SM, Wilson CB: Characterization of collagenase solubilized human glomerular basement membrane antigens reacting with human antibodies [Abstract]. Kidney Int 16: 797, 1979
  56. Foidart JB, Pirard YS, Winand RJ, Mahieu PR: Tissue culture of normal rat glomeruli: Glycosaminoglycan biosynthesis by homogeneous epithelial and mesangial cell populations. Ren Physiol 3: 169–173, 1980[Medline]
  57. Hunt JS, Macdonald PR, McGiven AR: Characterisation of human glomerular basement membrane antigenic fractions isolated by affinity chromatography utilising anti-glomerular basement membrane autoantibodies. Biochem Biophys Res Commun 104: 1025–1032, 1982[CrossRef][Medline]
  58. Wieslander J, Barr JF, Butkowski RJ, Edwards SJ, Bygren P, Heinegard D, Hudson BG: Goodpasture antigen of the glomerular basement membrane: Localization to noncollagenous regions of type IV collagen. Proc Natl Acad Sci U S A 81: 3838–3842, 1984[Abstract/Free Full Text]
  59. Wieslander J, Bygren P, Heinegard D: Isolation of the specific glomerular basement membrane antigen involved in Goodpasture syndrome. Proc Natl Acad Sci U S A 81: 1544–1548, 1984[Abstract/Free Full Text]
  60. Butkowski RJ, Wieslander J, Wisdom BJ, Barr JF, Noelken ME, Hudson BG: Properties of the globular domain of type IV collagen and its relationship to the Goodpasture antigen. J Biol Chem 260: 3739–3747, 1985[Abstract/Free Full Text]
  61. Kleppel MM, Michael AF, Fish AJ: Antibody specificity of human glomerular basement membrane type IV collagen NC1 subunits. Species variation in subunit composition. J Biol Chem 261: 16547–16552, 1986[Abstract/Free Full Text]
  62. Butkowski RJ, Langeveld JP, Wieslander J, Hamilton J, Hudson BG: Localization of the Goodpasture epitope to a novel chain of basement membrane collagen. J Biol Chem 262: 7874–7877, 1987[Abstract/Free Full Text]
  63. Hudson BG, Wieslander J, Wisdom BJ Jr, Noelken ME: Goodpasture syndrome: Molecular architecture and function of basement membrane antigen. Lab Invest 61: 256–269, 1989[Medline]
  64. Saus J, Wieslander J, Langeveld JP, Quinones S, Hudson BG: Identification of the Goodpasture antigen as the alpha 3(IV) chain of collagen IV. J Biol Chem 263: 13374–13380, 1988[Abstract/Free Full Text]
  65. Gunwar S, Saus J, Noelken ME, Hudson BG: Glomerular basement membrane. Identification of a fourth chain, alpha 4, of type IV collagen. J Biol Chem 265: 5466–5469, 1990[Abstract/Free Full Text]
  66. Morrison KE, Germino GG, Reeders ST: Use of the polymerase chain reaction to clone and sequence a cDNA encoding the bovine alpha 3 chain of type IV collagen. J Biol Chem 266: 34–39, 1991[Abstract/Free Full Text]
  67. Quinones S, Bernal D, Garcia-Sogo M, Elena SF, Saus J: Exon/intron structure of the human alpha 3(IV) gene encompassing the Goodpasture antigen (alpha 3(IV)NC1). Identification of a potentially antigenic region at the triple helix/NC1 domain junction. J Biol Chem 267: 19780–19784, 1992[Abstract/Free Full Text]
  68. Turner N, Mason PJ, Brown R, Fox M, Povey S, Rees A, Pusey CD: Molecular cloning of the human Goodpasture antigen demonstrates it to be the alpha 3 chain of type IV collagen. J Clin Invest 89: 592–601, 1992
  69. Feng L, Xia Y, Wilson CB: Alternative splicing of the NC1 domain of the human alpha 3(IV) collagen gene. Differential expression of mRNA transcripts that predict three protein variants with distinct carboxyl regions. J Biol Chem 269: 2342–2348, 1994[Abstract/Free Full Text]
  70. Mariyama M, Leinonen A, Mochizuki T, Tryggvason K, Reeders ST: Complete primary structure of the human alpha 3(IV) collagen chain. Coexpression of the alpha 3(IV) and alpha 4(IV) collagen chains in human tissues. J Biol Chem 269: 23013–23017, 1994[Abstract/Free Full Text]
  71. Kalluri R, Wilson CB, Weber M, Gunwar S, Chonko AM, Neilson EG, Hudson BG: Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome. J Am Soc Nephrol 6: 1178–1185, 1995[Abstract]
  72. Mariyama M, Kalluri R, Hudson BG, Reeders ST: The alpha 4(IV) chain of basement membrane collagen. Isolation of cDNAs encoding bovine alpha 4(IV) and comparison with other type IV collagens. J Biol Chem 267: 1253–1258, 1992[Abstract/Free Full Text]
  73. Leinonen A, Mariyama M, Mochizuki T, Tryggvason K, Reeders ST: Complete primary structure of the human type IV collagen alpha 4(IV) chain. Comparison with structure and expression of the other alpha (IV) chains. J Biol Chem 269: 26172–26177, 1994[Abstract/Free Full Text]
  74. Kleppel MM, Kashtan CE, Butkowski RJ, Fish AJ, Michael AF: Alport familial nephritis. Absence of 28 kilodalton non-collagenous monomers of type IV collagen in glomerular basement membrane. J Clin Invest 80: 263–266, 1987
  75. Boyd CD, Weliky K, Toth-Fejel S, Deak SB, Christiano AM, Mackenzie JW, Sandell LJ, Tryggvason K, Magenis E: The single copy gene coding for human alpha 1 (IV) procollagen is located at the terminal end of the long arm of chromosome 13. Hum Genet 74: 121–125, 1986[CrossRef][Medline]
  76. Griffin CA, Emanuel BS, Hansen JR, Cavenee WK, Myers JC: Human collagen genes encoding basement membrane alpha 1 (IV) and alpha 2 (IV) chains map to the distal long arm of chromosome 13. Proc Natl Acad Sci U S A 84: 512–516, 1987[Abstract/Free Full Text]
  77. Hostikka SL, Eddy RL, Byers MG, Hoyhtya M, Shows TB, Tryggvason K: Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc Natl Acad Sci U S A 87: 1606–1610, 1990[Abstract/Free Full Text]
  78. Myers JC, Jones TA, Pohjolainen ER, Kadri AS, Goddard AD, Sheer D, Solomon E, Pihlajaniemi T: Molecular cloning of alpha 5(IV) collagen and assignment of the gene to the region of the X chromosome containing the Alport syndrome locus. Am J Hum Genet 46: 1024–1033, 1990[Medline]
  79. Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K: Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248: 1224–1227, 1990[Abstract/Free Full Text]
  80. Mariyama M, Zheng K, Yang-Feng TL, Reeders ST: Colocalization of the genes for the alpha 3(IV) and alpha 4(IV) chains of type IV collagen to chromosome 2 bands q35–q37. Genomics 13: 809–813, 1992[CrossRef][Medline]
  81. Zhou J, Mochizuki T, Smeets H, Antignac C, Laurila P, de Paepe A, Tryggvason K, Reeders ST: Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors. Science 261: 1167–1169, 1993[Abstract/Free Full Text]
  82. Zhou J, Ding M, Zhao Z, Reeders ST: Complete primary structure of the sixth chain of human basement membrane collagen, alpha 6(IV). Isolation of the cDNAs for alpha 6(IV) and comparison with five other type IV collagen chains. J Biol Chem 269: 13193–13199, 1994[Abstract/Free Full Text]
  83. Oohashi T, Sugimoto M, Mattei MG, Ninomiya Y: Identification of a new collagen IV chain, alpha 6(IV), by cDNA isolation and assignment of the gene to chromosome Xq22, which is the same locus for COL4A5. J Biol Chem 269: 7520–7526, 1994[Abstract/Free Full Text]
  84. Oohashi T, Ueki Y, Sugimoto M, Ninomiya Y: Isolation and structure of the COL4A6 gene encoding the human alpha 6(IV) collagen chain and comparison with other type IV collagen genes. J Biol Chem 270: 26863–26867, 1995[Abstract/Free Full Text]
  85. Soininen R, Huotari M, Ganguly A, Prockop DJ, Tryggvason K: Structural organization of the gene for the alpha 1 chain of human type IV collagen. J Biol Chem 264: 13565–13571, 1989[Abstract/Free Full Text]
  86. Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C: Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12: 97–106, 2001[Abstract/Free Full Text]
  87. Boye E, Mollet G, Forestier L, Cohen-Solal L, Heidet L, Cochat P, Grunfeld JP, Palcoux JB, Gubler MC, Antignac C: Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am J Hum Genet 63: 1329–1340, 1998[CrossRef][Medline]
  88. Zhou J, Leinonen A, Tryggvason K: Structure of the human type IV collagen COL4A5 gene. J Biol Chem 269: 6608–6614, 1994[Abstract/Free Full Text]
  89. Zhang X, Zhou J, Reeders ST, Tryggvason K: Structure of the human type IV collagen COL4A6 gene, which is mutated in Alport syndrome-associated leiomyomatosis. Genomics 33: 473–479, 1996[CrossRef][Medline]
  90. Buttice G, Kaytes P, D’Armiento J, Vogeli G, Kurkinen M: Evolution of collagen IV genes from a 54-base pair exon: A role for introns in gene evolution. J Mol Evol 30: 479–488, 1990[CrossRef][Medline]
  91. Gunwar S, Noelken ME, Hudson BG: Properties of the collagenous domain of the alpha 3(IV) chain, the Goodpasture antigen, of lens basement membrane collagen. Selective cleavage of alpha (IV) chains with retention of their triple helical structure and noncollagenous domain. J Biol Chem 266: 14088–14094, 1991[Abstract/Free Full Text]
  92. Gunwar S, Ballester F, Noelken ME, Sado Y, Ninomiya Y, Hudson BG: Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of {alpha}3, {alpha}4 and {alpha}5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem 273: 8767–8775, 1998[Abstract/Free Full Text]
  93. Gunwar S, Ballester F, Kalluri R, Timoneda J, Chonko AM, Edwards SJ, Noelken ME, Hudson BG: Glomerular basement membrane. Identification of dimeric subunits of the noncollagenous domain (hexamer) of collagen IV and the Goodpasture antigen. J Biol Chem 266: 15318–15324, 1991[Abstract/Free Full Text]
  94. Borza DB, Bondar O, Ninomiya Y, Sado Y, Naito I, Todd P, Hudson BG: The NC1 domain of collagen IV encodes a novel network composed of the {alpha}1, {alpha}2, {alpha}5, and {alpha}6 chains in smooth muscle basement membranes. J Biol Chem 276: 28532–28540, 2001[Abstract/Free Full Text]
  95. Hudson BG, Kalluri R, Gunwar S, Weber M, Ballester F, Hudson JK, Noelken ME, Sarras M, Richardson WR, Saus J, et al.: The pathogenesis of Alport syndrome involves type IV collagen molecules containing the alpha 3(IV) chain: Evidence from anti-GBM nephritis after renal transplantation. Kidney Int 42: 179–187, 1992[Medline]
  96. Boutaud A, Borza DB, Bondar O, Gunwar S, Netzer KO, Singh N, Ninomiya Y, Sado Y, Noelken ME, Hudson BG: Type IV collagen of the glomerular basement membrane: Evidence that the chain specificity of network assembly is encoded by the noncollagenous NC1 domains. J Biol Chem 275: 30716–30724, 2000[Abstract/Free Full Text]
  97. Stanton MC, Tange JD: Goodpasture’s syndrome (pulmonary haemorrhage associated with glomerulonephritis). Aust Ann Med 7: 132–144, 1958
  98. Goodpasture EW: The significance of certain pulmonary lesions in relation to the etiology of influenza. Am J Med Sci 158: 863–870, 1919[CrossRef]
  99. Gunwar S, Bejarano PA, Kalluri R, Langeveld JP, Wisdom BJ Jr, Noelken ME, Hudson BG: Alveolar basement membrane: molecular properties of the noncollagenous domain (hexamer) of collagen IV and its reactivity with Goodpasture autoantibodies. Am J Respir Cell Mol Biol 5: 107–112, 1991
  100. Netzer KO, Leinonen A, Boutaud A, Borza DB, Todd P, Gunwar S, Langeveld JP, Hudson BG: The Goodpasture autoantigen. Mapping the major conformational epitope(s) of alpha3(IV) collagen to residues 17–31 and 127–141 of the NC1 domain. J Biol Chem 274: 11267–11274, 1999[Abstract/Free Full Text]
  101. Hellmark T, Burkhardt H, Wieslander J: Goodpasture disease. Characterization of a single conformational epitope as the target of pathogenic autoantibodies. J Biol Chem 274: 25862–25868, 1999[Abstract/Free Full Text]
  102. David M, Borza DB, Leinonen A, Belmont JM, Hudson BG: Hydrophobic amino acid residues are critical for the immunodominant epitope of the Goodpasture autoantigen. A molecular basis for the cryptic nature of the epitope. J Biol Chem 276: 6370–6377, 2001[Abstract/Free Full Text]
  103. Wieslander J, Langeveld J, Butkowski R, Jodlowski M, Noelken M, Hudson BG: Physical and immunochemical studies of the globular domain of type IV collagen. Cryptic properties of the Goodpasture antigen. J Biol Chem 260: 8564–8570, 1985[Abstract/Free Full Text]
  104. Borza DB, Netzer KO, Leinonen A, Todd P, Cervera J, Saus J, Hudson BG: The Goodpasture autoantigen: Identification of multiple cryptic epitopes on the NC1 domain of the alpha3(IV) collagen chain. J Biol Chem 275: 6030–6037, 2000[Abstract/Free Full Text]
  105. Stevenson A, Yaqoob M, Mason H, Pai P, Bell GM: Biochemical markers of basement membrane disturbances and occupational exposure to hydrocarbons and mixed solvents. QJM 88: 23–28, 1995
  106. Donaghy M, Rees AJ: Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet 2: 1390–1393, 1983[Medline]
  107. Kalluri R, Gattone VH 2nd, Noelken ME, Hudson BG: The alpha 3 chain of type IV collagen induces autoimmune Goodpasture syndrome. Proc Natl Acad Sci U S A 91: 6201–6205, 1994[Abstract/Free Full Text]
  108. Sado Y, Boutaud A, Kagawa M, Naito I, Ninomiya Y, Hudson BG: Induction of anti-GBM nephritis in rats by recombinant alpha 3(IV)NC1 and alpha 4(IV)NC1 of type IV collagen. Kidney Int 53: 664–671, 1998[CrossRef][Medline]
  109. Kalluri R, Cantley LG, Kerjaschki D, Neilson EG: Reactive oxygen species expose cryptic epitopes associated with autoimmune Goodpasture syndrome. J Biol Chem 275: 20027–20032, 2000[Abstract/Free Full Text]
  110. Kalluri R, Sun MJ, Hudson BG, Neilson EG: The Goodpasture autoantigen. Structural delineation of two immunologically privileged epitopes on alpha3(IV) chain of type IV collagen. J Biol Chem 271: 9062–9068, 1996[Abstract/Free Full Text]
  111. Alport AC: Hereditary familial congenital haemorrhagic nephritis. Br Med J 1: 504–506, 1927[Free Full Text]
  112. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC: X-linked alport syndrome: Natural history and genotype-phenotype correlations in girls and women belonging to 195 families: A "European Community Alport Syndrome Concerted Action" study. J Am Soc Nephrol 14: 2603–2610, 2003[Abstract/Free Full Text]
  113. Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC: X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11: 649–657, 2000[Abstract/Free Full Text]
  114. Kalluri R, Shield CF, Todd P, Hudson BG, Neilson EG: Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest 99: 2470–2478, 1997[Medline]
  115. Miner JH, Sanes JR: Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: Sequence, distribution, association with laminins, and developmental switches. J Cell Biol 127: 879–891, 1994[Abstract/Free Full Text]
  116. Harvey SJ, Zheng K, Sado Y, Naito I, Ninomiya Y, Jacobs RM, Hudson BG, Thorner PS: Role of distinct type IV collagen networks in glomerular development and function. Kidney Int 54: 1857–1866, 1998[CrossRef][Medline]



This article has been cited by other articles:


Home page
 NEJMHome page
L. H. Beck Jr., R. G.B. Bonegio, G. Lambeau, D. M. Beck, D. W. Powell, T. D. Cummins, J. B. Klein, and D. J. Salant
M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy
N. Engl. J. Med., July 2, 2009; 361(1): 11 - 21.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
O. Devuyst, I. Meij, X. Jeunemaitre, P. Ronco, C. Antignac, E. I. Christensen, N. V. Knoers, E. N. Levtchenko, P. M. Deen, D. Muller, et al.
EUNEFRON, the European Network for the Study of Orphan Nephropathies
Nephrol. Dial. Transplant., July 1, 2009; 24(7): 2011 - 2015.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
D. R. Abrahamson, B. G. Hudson, L. Stroganova, D.-B. Borza, and P. L. St. John
Cellular Origins of Type IV Collagen Networks in Developing Glomeruli
J. Am. Soc. Nephrol., July 1, 2009; 20(7): 1471 - 1479.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
P. S. Thorner, M. Ho, V. Eremina, Y. Sado, and S. Quaggin
Podocytes Contribute to the Formation of Glomerular Crescents
J. Am. Soc. Nephrol., March 1, 2008; 19(3): 495 - 502.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
K. Giannakakis, L. Massella, D. Grassetti, F. Dotta, M. Perez, and A. O. Muda
Type VII collagen in Alport syndrome
Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3501 - 3507.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
D. R. Abrahamson, P. L. St. John, K. Isom, B. Robert, and J. H. Miner
Partial Rescue of Glomerular Laminin {alpha}5 Mutations by Wild-Type Endothelia Produce Hybrid Glomeruli
J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2285 - 2293.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
C. E. Kashtan
Alport syndrome and the X chromosome: implications of a diagnosis of Alport syndrome in females
Nephrol. Dial. Transplant., June 1, 2007; 22(6): 1499 - 1505.
[Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
J. C. Wilson, H.-S. Yoon, R. J. Walker, and M. R. Eccles
A novel Cys1638Tyr NC1 domain substitution in {alpha}5(IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities
Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1338 - 1346.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
S. Sethi, M. Lewin, L. Lopez, and D. Lager
Linear anti-glomerular basement membrane IgG but no glomerular disease: Goodpasture's syndrome restricted to the lung
Nephrol. Dial. Transplant., April 1, 2007; 22(4): 1233 - 1235.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Liu, L. C. Clement, Y. S. Kanwar, C. Avila-Casado, and S. S. Chugh
ZHX Proteins Regulate Podocyte Gene Expression during the Development of Nephrotic Syndrome
J. Biol. Chem., December 22, 2006; 281(51): 39681 - 39692.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
G. Wei, L. Zhihong, C. Huiping, Z. Caihong, C. Zhaohong, and L. Leishi
Spectrum of clinical features and type IV collagen {alpha}-chain distribution in Chinese patients with Alport syndrome
Nephrol. Dial. Transplant., November 1, 2006; 21(11): 3146 - 3154.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
J. Su, Z.-H. Liu, C.-H. Zeng, Wei-Gong, H.-P. Chen, and L.-S. Li
Quantitative analysis of type IV collagen subchains in the glomerular basement membrane of patients with Alport syndrome with confocal microscopy
Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1838 - 1847.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
C. El-Aouni, N. Herbach, S. M. Blattner, A. Henger, M. P. Rastaldi, G. Jarad, J. H. Miner, M. J. Moeller, R. St-Arnaud, S. Dedhar, et al.
Podocyte-Specific Deletion of Integrin-Linked Kinase Results in Severe Glomerular Basement Membrane Alterations and Progressive Glomerulosclerosis
J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1334 - 1344.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
C. Kashtan
Autotopes and Allotopes
J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3455 - 3457.
[Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
J. E. Wiggins, M. Goyal, S. K. Sanden, B. L. Wharram, K. A. Shedden, D. E. Misek, R. D. Kuick, and R. C. Wiggins
Podocyte Hypertrophy, "Adaptation," and "Decompensation" Associated with Glomerular Enlargement and Glomerulosclerosis in the Aging Rat: Prevention by Calorie Restriction
J. Am. Soc. Nephrol., October 1, 2005; 16(10): 2953 - 2966.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. M. Vanacore, D. B. Friedman, A.-J. L. Ham, M. Sundaramoorthy, and B. G. Hudson
Identification of S-Hydroxylysyl-methionine as the Covalent Cross-link of the Noncollagenous (NC1) Hexamer of the {alpha}1{alpha}1{alpha}2 Collagen IV Network: A ROLE FOR THE POST-TRANSLATIONAL MODIFICATION OF LYSINE 211 TO HYDROXYLYSINE 211 IN HEXAMER ASSEMBLY
J. Biol. Chem., August 12, 2005; 280(32): 29300 - 29310.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hudson, B. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hudson, B. G.

HOME CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP