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|Mutation Type||critical splice donor site (1 bp from exon)|
|Coordinate||82,535,740 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||collagen, type IV, alpha 4|
|Chromosomal Location||82,448,423-82,586,849 bp (-)|
|MGI Phenotype||Mice homozygous for an ENU-induced mutation develop an early nephritic syndrome associated with uremia, proteinuria, hematuria, leukocyturia, and focal segmental glomerulosclerosis, and die prematurely of kidney failure. Some homozygotes exhibit moderatesensorineural hearing loss.|
|Amino Acid Change|
|Institutional Source||Beutler Lab|
Ensembl: ENSMUSP00000084282 (fasta)
|Gene Model||not available|
|Phenotypic Category||digestive/alimentary, hearing/vestibular/ear, renal/urinary system|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||05/13/2016 3:09 PM by Stephen Lyon|
|Other Mutations in This Stock||
Stock #: N/A - 293 Run Code:
Validation Efficiency: 165/193
The aoba phenotype was identified while screening G3 mice homozygous for random mutations induced by N-ethyl-N-nitrosourea (ENU) for susceptibility to non-lethal doses of mouse cytomegalovirus (MCMV) (MCMV Susceptibility and Resistance Screen). Spontaneous death was observed in one pedigree. Homozygous aoba mice are generally healthy and fertile, although slightly leaner than wild type animals. However, they spontaneously die between six to seven months of age with death occurring under specific pathogen free (SPF) conditions. Moribund animals display dramatically elevated levels of blood urea nitrogen (BUN) and creatinine (Figure 1), and small, pale kidneys with focal glomerusclerosis (Figure 2), consistent with end-stage renal disease (ESRD) and kidney failure. Proteinuria (Table I), hematuria (Table II), and leukocytes in the urine (Table III) could be detected in aoba mice as early as two months of age. In addition, these animals exhibited enlarged stomachs containing undigested food (1).
Table I. Proteinuria in wildtype and Aoba mice
aAll wildtype mice (2-5 per age group, 14 total) were negative for proteinuria.
bUrine could not be collected from 2 additional 5-month-old mice.
Table II. Hematuria in wildtype and Aoba mice
aAll wildtype mice (2-5 per age group, 13 total) were negative for hematuria.
Table III. Presence of leukocytes in urine from wildtype and Aoba mice
aAll wildtype mice (2-5 per age group, 13 total) were negative for the presence of leukocytes in the blood.
Some aoba mice display moderate sensorineural hearing loss with an increased threshold for auditory brain stem response (ABR), but this phenotype has low penetrance (Figure 3).
|Nature of Mutation|
Whole genome sequencing of a homozygous aoba mouse using the SOLiD technique was performed (1). Briefly, genomic DNA was sheared into 100 to 110 bp fragments, ligated to P1 and P2 adaptors, and amplified using library primers. The resulting short fragment DNA library was then clonally amplified onto SOLiD P1 DNA beads and templated beads were loaded onto two slides and subjected to SOLiD sequencing through an extension length of 50 bp fragment reads. Reads were mapped to the reference genome (C57BL/6J assembly Build 37) with a maximum of 6 mismatches allowed for each read. After subtracting mismatches, 88.5%, 82.5%, and 74.56% of coding/splicing sequence was covered at least 1X, 2X or 3X, respectively. Validation sequencing using the Sanger method was attempted on all nucleotides for which discrepancies were seen at 3x or greater coverage, with 132 of 146 discrepancies successfully processed.
Whole genome SOLiD sequencing followed by Sanger sequencing validation identified a total of 11 mutations in aoba mice, one of which occurred in the Col4a4 candidate gene (Figure 4A). This was a G to A transition at position 82,532,315in the Genbank genomic region NC_000067 for the Col4a4 gene on chromosome 1 (GTAAGTTTTA -> ATAAGTTTTA). The mutation is located within intron 8, one nucleotide downstream from the previous exon 8, and impairs the donor splice site of intron 8. Reverse transcription and PCR amplification revealed a deletion of 8 nucleotides within the aoba Col4a4 cDNA, resulting in a frame-shift, the addition of 13 aberrant amino acids after residue 176, and a premature stop codon. Col4a4 contains 48 exons. Multiple Col4a4 transcripts are displayed on Ensembl.
<--exon 7 <--exon 8 intron 8--> exon 9--> <--exon 10
47754 GGCCCCCCT……GTTAAAGGT ATTCAG GTAAGTTTT………GGAGACCG…………GGATCTAG 55167
153 -G--P--P-……-V--K--G- -I--Q- -R--P-………………-I--*- 189
correct deleted aberrant
The donor splice site of intron 8, which is destroyed by the aoba mutation, is indicated in blue lettering; the mutated nucleotide is indicated in red lettering. The 8 deleted nucleotides are highlighted in gray.
In order to validate that the aoba mutation was causing end stage renal disease in aoba mice, mapping was performed by outcrossing homozygous animals to the closely related C57BL/10J strain and intercrossing F1 animals to yield F2 mice. Proteinuria was measured in four to five month-old animals and the DNA samples from 17 phenotypically mutant and 28 phenotypically normal animals were isolated and quantitated by real-time PCR. Equal amounts of DNA from each mutant and WT mouse were added to separate pools and subjected to bulk segregation analysis (BSA) using a total of 127 SNPs that distinguish the C57BL/6J and C57BL/10J strains. C57BL/6J and C57BL/10J allele frequencies were calculated based on normalized capillary sequencing chromatogram peak heights, which reflect the quantity of a given nucleotide at each position in the DNA sequence (2). BSA localized the aoba mutation to a ~43 Mb region on chromosome 1, with LOD scores of 7.1, 8.9, and 10 at markers 75,483,331; 95,571,814; and 118,565,405, respectively (Figure 4B). This result was confirmed by genotyping individual F2 mice for the C57BL/6J and C57BL/10J alleles of each of these markers. The LOD scores calculated from this analysis were 5.9, 10.2, and 10.2 at markers 75,483,331; 95,571,814; and 118,565,405, respectively. As the Col4a4 mutation is located at 82,532,315 on chromosome 1, it is likely to be responsible for kidney disease in aoba mice. The adjacent Col4a3 candidate gene was excluded by sequencing (1).
The Col4a4 gene encodes a 1682 amino acid member of the type IV collagen family. In vertebrates, the collagen superfamily contains 28 different types of collagen (3;4). The type IV collagen family includes six highly homologous α-chains, α1-α6. Each chain contains three structurally distinct domains; an N-terminal domain of about 140 amino acids rich in cysteine and lysine residues (known as the 7S domain), a collagenous domain of about 1300 residues largely composed of Gly-Xaa-Yaa repeats, and a C-terminal noncollagenous (NC1) domain that is roughly 230 amino acids long (Figure 5). Based on sequence homology, these six α-chains can be divided into two groups; the α1, α3, and α5 chains, and the α2, α4, α6 chains. Type IV collagen α-chains form heterotrimers to make up single collagen molecules. In turn, collagen heterotrimers dimerize through their NC1 domains and form tetramers through their 7S domains to form a collagen network (3;5-7) (Figure 6).
Type IV collagen α-chains are processed into mature form and secreted extracellularly where they form collagen networks. Like other collagens, collagen IV undergoes many posttranslational modifications (4). These include removal of the signal peptide in the endoplasmic reticulum (ER), hydroxylation of many proline and lysine residues, glycosylation of specific hydroxylysine residues, addition of mannose-rich oligosachharide and the formation of important intrachain disulfide bonds between 12 conserved cysteine residues in the NC1 domain. Biosynthesis of collagen is highly dependent on at least one specific molecular chaperone, Hsp47 (8;9). In collagen IV, N-linked oligosaccharides are located in the 7S domain and hydroxylysine linked disaccharides are scattered along the entire molecule. These posttranslational modifications likely provide specificity to the alignment and assembly of collagen IV networks (10).
In the Gly-Xaa-Yaa repeats found in the large collagenous domain, X and Y are often proline and hydroxyproline residues. These sequences have a high propensity to form supercoiled triple helical structures (11). Type IV collagen collagenous domains contain numerous interruptions in the repeat motifs that provide molecular flexibility to the collagen networks, and may provide sites for cell-binding and interchain crosslinking (12). All type IV collagen α-chains contain numerous RGD motifs that are known to be integrin-binding sites. However, extensive data on the binding of various integrins to α1, α2, and α3 suggest that these interactions are mostly RGD-independent (3;13;14).
Of all the α-chains, α4 contains the most interruptions in the collagenous domain with a total of 26, and in addition contains the most cysteine residues in its collagenous and 7S domains. Thus, the α3 α4 α5 collagen network has distinct biological properties from the other type IV collagen networks due to a larger number of inter- and intrachain disulfide bonds (24) (see Background).
The aoba mutation destroys the donor splice site of intron 8, deletes 8 nucleotides from the Col4a4 cDNA, and results in premature protein truncation.
In mice, the collagen IV α4 chain is highly expressed in kidney and lung and detected at lower levels in heart, muscle and skin. Colocalization with α3 and α5 occurs in the glomerular basement membrane (GBM), and tubular basement membrane (TBM) of the kidney, as well as synaptic basal lamina (25). α3, α4, and α5 are expressed in and secreted by the podocytes of the kidney (26). α4 is expressed in the conjunctival basement membrane of the eye (27), in some of the basement membranes of developing tooth buds (28), and is found in the inner ear (29). Examining the collagen IV expression patterns during the development of several tissues in the mouse reveals that the basement membranes of several tissues undergo a developmental shift in collagen expression. During early development of the lens capsule, the testis, and the GBM, the type IV collagen expressed in these tissues is α1 and α2. As these tissues differentiate, the α1 α1 α2 network is replaced with α3, α4, and α5 (25;30-32). In dogs, a similar switch has been noted during inner ear development (33).
In humans, Northern blot analysis found high expression of COL4A4 mRNA in adult human kidney, skeletal muscle, and lung, and in fetal kidney and lung with weaker expression in fetal heart. Expression of COL4A4 largely overlapped that of COL4A3 (34). α4 is also expressed in the retinal pigment epithelial basement membrane and the lens capsule (32;35), as well as the inner ear (36). As in mice, there is a developmental switch in collagen expression in certain basement membranes from α1 and α2 to α3, α4, and α5 (30;32;37).
The basement membrane (BM) is a highly specialized extracellular matrix (ECM) containing collagen IV, laminins, nidogen and sulfated proteoglycans that lies beneath epithelial and endothelial cells and surrounds muscles, nerves, adipocytes and smooth muscle cells. The laminin polymers found in the BM function as the initial template for assembly (38). In the trans-Golgi network (TGN), collagen type IV chains form heterotrimeric protomers. These protomers are then secreted extracellularly, where they associate to form a supramolecular structure, mediated by cell surface integrins and/or by binding interactions with laminin and other BM-associated macromolecules (3;5). The highly ordered and crosslinked nature of type IV collagen networks endows BMs with their structural integrity (5). The BM has a wide variety of biological activities such as providing adherent cells with structural support and functional cues through its biomechanical properties, and the presence of adhesion receptor ligands and matrix-bound growth factors. BMs also prevent the diffusion of all but the smallest molecules. However, normal and cancerous cells can interact via integrin cell surface receptors to mediate cell adhesion and initiate tissue-invasive mechanisms including the expression of ECM-degradative proteases such as certain matrix metalloproteases (5).
Basement membranes play an important role in the structure and function of the kidney. The kidney is the site of plasma filtration, which occurs in the renal glomeruli (Figure 9). The glomeruli are made up of tufts of capillaries composed of a defined basement membrane known as the glomerular basement membrane (GMB), which is lined on one side by fenestrated endothelium facing the blood and on the other side by a specialized epithelium facing the urinary space. The specialized cells of the epithelium have long and extensive foot processes, and are known as podocytes. The glomerular basement membrane (GBM) and the glomerular epithelial slit diaphragms (GESD) provide barriers to proteins larger than 70 kDa. The GESD is a modified adherens junction between the foot processes of the podocyte, and may be the most important barrier for preventing protein leak into the urine (39).
Alport syndrome (OMIM #301050; #203780) is an inherited progressive disease of the kidneys, often associated with sensorineural deafness and occasionally ocular lesions. The renal disease becomes evident as recurrent microscopic or gross hematuria, sometimes in childhood, and progresses to end-stage renal disease (ESRD). Patients can exhibit extensive glomerusclerosis. Alport syndrome shows considerable clinical heterogeneity, with X-linked forms of the disease caused by mutations in the COL4A5 gene, and autosomal recessive and dominant forms caused by mutations in COL4A3 and COL4A4 (40-42). Heterozygous mutations in COL4A3 and COL4A4 also result in autosomal dominant benign familial hematuria (BFH; OMIM #141200) or thin basement membrane nephropathy (TBMN), which presents with microscopic hematuria, but only occasionally progresses to kidney malfunction (41;43). Both Alport syndrome and BFH can be considered to be genetic diseases of the glomerular basement membrane (GBM) of the kidney, with Alport patients displaying variable thinning and thickening of the GBM, combined with multilamellation of the lamina densa. Individuals diagnosed with BFH are characterized by less severe changes in the GBM (42). Since the α3, α4, α5 chains form a trimeric molecule, a mutation in any of these chains usually results in complete absence of the α3 α4 α5 collagen IV network (42;44).
Animal models of Alport syndrome include spontaneous mutations found in the Col4a5 gene in dogs (45;46), as well as mouse knockouts of Col4a3 and Col4a5 (47-49). An additional mouse containing a transgenic insertion that results in a genomic DNA deletion encompassing portions of the Col4a3 and Col4a4 genes and their shared promoter, has been described (50). All of these animal models exhibit GBM abnormalities progressing to end-stage renal disease, mirroring the phenotypes displayed in human patients. Like the human disease, the course of disease progression and age of kidney failure in these animal models can vary greatly. C57BL/6J Col4a3?/- mice, compared with mice on a 129/SvJ background, have a significantly delayed disease onset with end-stage renal failure occurring at 194 versus 66 days on average (51). The difference in disease progression can be partially attributed to the ectopic deposition of the collagen IV α5 and α6 chains in the GBM of knockout mice on the C57BL/6J background, whereas only the α1 and α2 chains were present in the GBM of Col4a3 knockouts on the 129/SvJ background (52).
The initial function of the GBM in both humans and animals with Alport syndrome appears to be retained, likely due to the persistence of an embryonic-like α1 α1 α2 collagen network in place of α3 α4 α5 (30). Differences between the physical and biological properties of the α1 α1 α2 network vs. the α3 α4 α5 network are likely to underlie the inability of the former to compensate for the lack of the latter. The α3 and α4 chains are more cysteine-rich than α1 and α2, allowing loop structures to form between triple helical collagen molecules. Thus, the α3 α4 α5 may provide more structural integrity to the GBM that is needed for appropriate plasma filtration. In addition, the α1 α1 α2 network is more susceptible to degradation by proteases it encounters in the serum. The uneven thickness of the GBM characteristic of Alport syndrome is likely due to gradual proteolytic degradation of the α1 α1 α2 network found in these patients (3;24;42). The proteolytic degradation of the GBM appears to be enhanced by the increased expression of matrix metalloprotease-12 (MMP12), found in the podocytes of animals and humans with Alport syndrome (53). Increased expression of MMP2, MMP9, as well as TGFβ1, have been found to contribute to the progressive fibrosis found in patients with Alport syndrome (54;55).
Mouse knockouts of certain integrin receptors also exhibit similar kidney phenotypes. Integrin receptors are heterodimers composed of an α- and a β-subunit. 18α- and 8β-subunits have been identified in mammalian cells (3). The predominant integrin expressed by podocytes is α3β1 (56), and in vivo deletion of the α3 subunit results in a strong glomerular phenotype (57). Although integrins α1β1 and α2β1 are also expressed by podocytes, their role in normal glomerular development is likely to be less important, as mice null for the α1 or α2 subunit only have a minor glomerular phenotype (14;58). The αvβ3 integrin is also expressed in podocytes and has been demonstrated to bind to the collagen IV α3 chain. However, deletion of this integrin in mice did not induce renal abnormalities, although increased expression of integrin αvβ3 is associated with diabetic nephropathy (59). In addition to integrin receptors, the discoidin domain receptors (DDRs) have also been found to bind to collagens (60), and deletion of DDR1 in mice results in GBM thickening and proteinuria (61).
Other diseases associated with collagen IV include Goodpasture’s syndrome (OMIM #233450), and the rare neurological disease encephaloclastic porencephaly (OMIM #175780). Encephaloclastic porencephaly is caused by mutations in the COL4A1 gene (62). Goodpasture’s syndrome is an autoimmune disease caused by autoantibodies directed against the collagen IV α3 chain, and is characterized by a rapidly progressive glomerulonephritis and lung hemorrhage (63). Two dominant epitopes on the α3 chain have been identified, but do not normally show reactivity to the antibodies unless the NC1 hexamer is dissociated (23). It is likely that environmental factors may cause this exposure, leading to the development of autoantibodies, and an immune reaction resulting in disruption of the glomerular filtration barrier [reviewed by (3)]. In insects, collagen IV peptide fragments constitute a danger system and stimulate the immune system, particularly fragments containing the integrin-binding motif, RGD (64). Collagen fragments appear to have functional roles in other systems as well. The NC1 domains of certain collagens, including the collagen IV α1, α2, α3 and α6 chains, have been discovered to contain anti-angiogenic and anti-tumorigenic properties. The proteolytic release of these soluble NC1 fragments stimulates migration, proliferation, apoptosis or survival of different cell types, and can even alter morphogenetic events. These events are likely to be mediated by interactions with various integrin receptors [reviewed by (3;7)]. None of these studies identified a similar role for the collagen IV α4 NC1 domain (65).
The collagen IV genes are arranged in three pairs in a head-to-head orientation, and are transcribed in opposite directions with COL4A1 paired with COL4A2, COL4A3 with COL4A4, and COL4A5 with COL4A6. This allows for coordinate regulation of the gene pairs in specific tissues. The LIM homeodomain transcription factor, LMX1b, is known to regulate the expression of Col4a3/Col4a4 in the GBM, and Lmx1b -/- animals and patients with heterozygous mutations in the LMX1B gene display kidney phenotypes similar to those described for Alport syndrome (OMIM #161200) (66). However, the regulation of the promoter sequences for these genes is not well understood, and differences in mRNA levels and proteins in certain tissues have been reported. Some examples include the expression of collagen IV α4 protein during early tooth morphogenesis and in the conjunctival basement membrane during eye development, in the absence of the α3 chain (27;28). Similarly, the α3 protein was reported in the adult corneal basement membrane of the eye where α4 was undetectable (27). In addition, α3 has several alternatively spliced variants that are expressed in human kidneys, while no splice variants have been reported for any of the other chains (67;68). The role of these splice variants in the collagen network is unknown.
The aoba mouse is the first known instance of a causative mutation identified by whole-genome high through-put sequencing. Aoba mice demonstrate a highly similar phenotype to other mouse and animal models of Alport syndrome (69), with spontaneous death occurring due to renal failure. Histological, blood and urine analyses revealed the typical phenotypes of humans and animals with Alport syndrome; focal glomerusclerosis and elevated levels of blood urea nitrogen. End-stage renal disease in these animals occurs at six to seven months of age, a similar time point as the renal failure observed in Col4a3 knockout mice on a C57BL/6J background (51). Considering the similarity between homozygous aoba mice and other mouse models of Alport syndrome, it is likely that the aoba mutation located in the donor splice site of intron 8 results in a profound loss of Col4a4 function.
Along with the mutation in Col4a4, homozygous aoba mice also display homozygous mutations in nine additional genes; Gm7271, Gm7634, Kras, Lrig1, Mycbp2, Olfr13, Smarcad1, Sprr4, and Zeb1 (Table 1), and it is possible that other ENU induced mutations exist but were not detected in the course of SOLiD sequencing and/or the validation sequencing that followed. A number of these genes have been knocked out in mice, and none of the phenotypes have been identified in aoba animals. It is likely that the function of the proteins encoded by these genes remain at least partially intact in aoba mice.
Zeb1, which is mutated in aoba, encodes a transcriptional repressor (TCF8) of the COL4A3 gene. In humans, mutations in ZEB1 result in posterior polymorphous corneal dystrophy-3 (PPCD3; OMIM #609141), a rare disorder involving metaplasia and overgrowth of corneal endothelial cells, as well as basement membrane abnormalities in the cornea. The overgrowth coincides with ectopic expression of COL4A3 by corneal endothelial cells, and a binding site for TCF8 was also identified in the COL4A3 promoter (79). Rare cases of PPCD have also been described in humans with Alport syndrome (80). In one patient with autosomal recessive Alport syndrome, corneal endothelial cells were attenuated and focally lost (81), a phenotype essentially the opposite of that found in patients carrying ZEB1 mutations. It is possible that aoba mice carrying a mutation in the Zeb1 gene, may display ectopic or overexpression of Col4a3, which may somehow affect the phenotypes caused by lack of Col4a4 function. However, the interdependence of the collagen IV α3 α4 α5 collagen network on each α-chain suggests that overexpression of α3 would not compensate for the lack of α4. In addition, as noted above, it is likely that TCF8 protein function in these animals is somewhat intact considering that they do not exhibit the same phenotypes as those found in Zeb1 knockout animals. Interestingly, overexpression of α3 and α4 in the lens of transgenic mice resulted in cataracts caused by the accumulation of collagen chains in the secretory pathway, and the activation of the stress signaling pathway known as the unfolded protein response (UPR; see the record for woodrat) (82).
|Primers||Primers cannot be located by automatic search.|
Aoba genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
aoba(F): 5’- ATGAAAACCTTGGACCTCAGGCTG -3’
aoba(R): 5’- GTCTCAGAGGCAAGGCAATCTACAG -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
aoba_seq(F): same as aoba(F)
aoba_seq(R): 5’- GGCAATCTACAGCCAGAGACTAAG -3’
The following sequence of 434 nucleotides (NCBI Mouse Genome Build 37.1, Chromosome 1, bases 82,532,111 to 82,532,544) is amplified:
atgaaaa ccttggacct caggctgata acaatcaagg agaccataat tccatcccag
tgaaatggct acagtgcttt ttactggtga ctaatatttc atatagaaga gaaaatactg
aaatggcagc ctactttttc ctaagtgaat gtctcctttt cagggtcagc ctggggaaaa
tggagaaaaa ggaagatctg tgtacattac tggtggcgtt aaaggtattc aggtaagttt
tatggccatt gtgcgtttga caaagccatt ttcccaatag gaaacacacg ggcagggatt
ttctataaag tattattgga tgtactgatt tattttattt tactttgcca ttaacctcat
acaacagatg gctctgttcc ccttgtggag aggcatgggc cttagtctct ggctgtagat
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated G is indicated in red.
1. Arnold, C. N., Xia, Y., Lin, P., Ross, C., Schwander, M., Smart, N. G., Müller, U., and Beutler, B. (2011) Rapid Identification of a Disease Allele in Mouse through Whole Genome Sequencing and Bulk Segregation Analysis. Genetics 187, 633-41.
2. Xia, Y., Won, S., Du, X., Lin, P., Ross, C., La Vine, D., Wiltshire, S., Leiva, G., Vidal, S. M., Whittle, B., Goodnow, C. C., Koziol, J., Moresco, E. M., and Beutler, B. (2010) Bulk Segregation Mapping of Mutations in Closely Related Strains of Mice. Genetics 186, 1139-1146.
3. Khoshnoodi, J., Pedchenko, V., and Hudson, B. G. (2008) Mammalian Collagen IV. Microsc. Res. Tech. 71, 357-370.
4. Myllyharju, J., and Kivirikko, K. I. (2004) Collagens, Modifying Enzymes and their Mutations in Humans, Flies and Worms. Trends Genet. 20, 33-43.
5. Rowe, R. G., and Weiss, S. J. (2008) Breaching the Basement Membrane: Who, when and how? Trends Cell Biol. 18, 560-574.
6. Reiser, K., McCormick, R. J., and Rucker, R. B. (1992) Enzymatic and Nonenzymatic Cross-Linking of Collagen and Elastin. FASEB J. 6, 2439-2449.
7. Ortega, N., and Werb, Z. (2002) New Functional Roles for Non-Collagenous Domains of Basement Membrane Collagens. J. Cell. Sci. 115, 4201-4214.
8. Nagai, N., Hosokawa, M., Itohara, S., Adachi, E., Matsushita, T., Hosokawa, N., and Nagata, K. (2000) Embryonic Lethality of Molecular Chaperone hsp47 Knockout Mice is Associated with Defects in Collagen Biosynthesis. J. Cell Biol. 150, 1499-1506.
9. Matsuoka, Y., Kubota, H., Adachi, E., Nagai, N., Marutani, T., Hosokawa, N., and Nagata, K. (2004) Insufficient Folding of Type IV Collagen and Formation of Abnormal Basement Membrane-Like Structure in Embryoid Bodies Derived from Hsp47-Null Embryonic Stem Cells. Mol. Biol. Cell. 15, 4467-4475.
10. Langeveld, J. P., Noelken, M. E., Hard, K., Todd, P., Vliegenthart, J. F., Rouse, J., and Hudson, B. G. (1991) Bovine Glomerular Basement Membrane. Location and Structure of the Asparagine-Linked Oligosaccharide Units and their Potential Role in the Assembly of the 7 S Collagen IV Tetramer. J. Biol. Chem. 266, 2622-2631.
11. Jenkins, C. L., and Raines, R. T. (2002) Insights on the Conformational Stability of Collagen. Nat. Prod. Rep. 19, 49-59.
12. Vandenberg, P., Kern, A., Ries, A., Luckenbill-Edds, L., Mann, K., and Kuhn, K. (1991) Characterization of a Type IV Collagen Major Cell Binding Site with Affinity to the Alpha 1 Beta 1 and the Alpha 2 Beta 1 Integrins. J. Cell Biol. 113, 1475-1483.
13. Herbst, T. J., McCarthy, J. B., Tsilibary, E. C., and Furcht, L. T. (1988) Differential Effects of Laminin, Intact Type IV Collagen, and Specific Domains of Type IV Collagen on Endothelial Cell Adhesion and Migration. J. Cell Biol. 106, 1365-1373.
14. Borza, C. M., Borza, D. B., Pedchenko, V., Saleem, M. A., Mathieson, P. W., Sado, Y., Hudson, H. M., Pozzi, A., Saus, J., Abrahamson, D. R., Zent, R., and Hudson, B. G. (2008) Human Podocytes Adhere to the KRGDS Motif of the alpha3alpha4alpha5 Collagen IV Network. J. Am. Soc. Nephrol. 19, 677-684.
15. Boutaud, A., Borza, D. B., Bondar, O., Gunwar, S., Netzer, K. O., Singh, N., Ninomiya, Y., Sado, Y., Noelken, M. E., and Hudson, B. G. (2000) 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.
16. Borza, D. B., Bondar, O., Ninomiya, Y., Sado, Y., Naito, I., Todd, P., and Hudson, B. G. (2001) 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.
17. Khoshnoodi, J., Cartailler, J. P., Alvares, K., Veis, A., and Hudson, B. G. (2006) Molecular Recognition in the Assembly of Collagens: Terminal Noncollagenous Domains are Key Recognition Modules in the Formation of Triple Helical Protomers. J. Biol. Chem. 281, 38117-38121.
18. Khoshnoodi, J., Sigmundsson, K., Cartailler, J. P., Bondar, O., Sundaramoorthy, M., and Hudson, B. G. (2006) Mechanism of Chain Selection in the Assembly of Collagen IV: A Prominent Role for the alpha2 Chain. J. Biol. Chem. 281, 6058-6069.
19. Sundaramoorthy, M., Meiyappan, M., Todd, P., and Hudson, B. G. (2002) Crystal Structure of NC1 Domains. Structural Basis for Type IV Collagen Assembly in Basement Membranes. J. Biol. Chem. 277, 31142-31153.
20. Than, M. E., Henrich, S., Huber, R., Ries, A., Mann, K., Kuhn, K., Timpl, R., Bourenkov, G. P., Bartunik, H. D., and Bode, W. (2002) 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.
21. Vanacore, R. M., Friedman, D. B., Ham, A. J., Sundaramoorthy, M., and Hudson, B. G. (2005) Identification of S-Hydroxylysyl-Methionine as the Covalent Cross-Link of the Noncollagenous (NC1) Hexamer of the alpha1alpha1alpha2 Collagen IV Network: A Role for the Post-Translational Modification of Lysine 211 to Hydroxylysine 211 in Hexamer Assembly. J. Biol. Chem. 280, 29300-29310.
22. Vanacore, R. M., Ham, A. J., Cartailler, J. P., Sundaramoorthy, M., Todd, P., Pedchenko, V., Sado, Y., Borza, D. B., and Hudson, B. G. (2008) A Role for Collagen IV Cross-Links in Conferring Immune Privilege to the Goodpasture Autoantigen: Structural Basis for the Crypticity of B Cell Epitopes. J. Biol. Chem. 283, 22737-22748.
23. Borza, D. B., Bondar, O., Todd, P., Sundaramoorthy, M., Sado, Y., Ninomiya, Y., and Hudson, B. G. (2002) Quaternary Organization of the Goodpasture Autoantigen, the Alpha 3(IV) Collagen Chain. Sequestration of Two Cryptic Autoepitopes by Intrapromoter Interactions with the alpha4 and alpha5 NC1 Domains. J. Biol. Chem. 277, 40075-40083.
24. Gunwar, S., Ballester, F., Noelken, M. E., Sado, Y., Ninomiya, Y., and Hudson, B. G. (1998) Glomerular Basement Membrane. Identification of a Novel Disulfide-Cross-Linked Network of alpha3, alpha4, and alpha5 Chains of Type IV Collagen and its Implications for the Pathogenesis of Alport Syndrome. J. Biol. Chem. 273, 8767-8775.
25. Miner, J. H., and Sanes, J. R. (1994) 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.
26. Abrahamson, D. R., Hudson, B. G., Stroganova, L., Borza, D. B., and St John, P. L. (2009) Cellular Origins of Type IV Collagen Networks in Developing Glomeruli. J. Am. Soc. Nephrol. 20, 1471-1479.
27. Qin, P., Piechocki, M., Lu, S., and Kurpakus, M. A. (1997) Localization of Basement Membrane-Associated Protein Isoforms during Development of the Ocular Surface of Mouse Eye. Dev. Dyn. 209, 367-376.
28. Nagai, N., Nakano, K., Sado, Y., Naito, I., Gunduz, M., Tsujigiwa, H., Nagatsuka, H., Ninomiya, Y., and Siar, C. H. (2001) Localization of Type IV Collagen a 1 to a 6 Chains in Basement Membrane during Mouse Molar Germ Development. Int. J. Dev. Biol. 45, 827-831.
29. Cosgrove, D., Kornak, J. M., and Samuelson, G. (1996) Expression of Basement Membrane Type IV Collagen Chains during Postnatal Development in the Murine Cochlea. Hear. Res. 100, 21-32.
30. Harvey, S. J., Zheng, K., Sado, Y., Naito, I., Ninomiya, Y., Jacobs, R. M., Hudson, B. G., and Thorner, P. S. (1998) Role of Distinct Type IV Collagen Networks in Glomerular Development and Function. Kidney Int. 54, 1857-1866.
31. Enders, G. C., Kahsai, T. Z., Lian, G., Funabiki, K., Killen, P. D., and Hudson, B. G. (1995) Developmental Changes in Seminiferous Tubule Extracellular Matrix Components of the Mouse Testis: Alpha 3(IV) Collagen Chain Expressed at the Initiation of Spermatogenesis. Biol. Reprod. 53, 1489-1499.
32. Kelley, P. B., Sado, Y., and Duncan, M. K. (2002) Collagen IV in the Developing Lens Capsule. Matrix Biol. 21, 415-423.
33. Harvey, S. J., Mount, R., Sado, Y., Naito, I., Ninomiya, Y., Harrison, R., Jefferson, B., Jacobs, R., and Thorner, P. S. (2001) The Inner Ear of Dogs with X-Linked Nephritis Provides Clues to the Pathogenesis of Hearing Loss in X-Linked Alport Syndrome. Am. J. Pathol. 159, 1097-1104.
34. Mariyama, M., Leinonen, A., Mochizuki, T., Tryggvason, K., and Reeders, S. T. (1994) 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.
35. Chen, L., Miyamura, N., Ninomiya, Y., and Handa, J. T. (2003) Distribution of the Collagen IV Isoforms in Human Bruch's Membrane. Br. J. Ophthalmol. 87, 212-215.
36. Merchant, S. N., Burgess, B. J., Adams, J. C., Kashtan, C. E., Gregory, M. C., Santi, P. A., Colvin, R., Collins, B., and Nadol, J. B.,Jr. (2004) Temporal Bone Histopathology in Alport Syndrome. Laryngoscope. 114, 1609-1618.
37. Kalluri, R., Shield, C. F., Todd, P., Hudson, B. G., and Neilson, E. G. (1997) 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.
38. McKee, K. K., Harrison, D., Capizzi, S., and Yurchenco, P. D. (2007) Role of Laminin Terminal Globular Domains in Basement Membrane Assembly. J. Biol. Chem. 282, 21437-21447.
39. Hamano, Y., Grunkemeyer, J. A., Sudhakar, A., Zeisberg, M., Cosgrove, D., Morello, R., Lee, B., Sugimoto, H., and Kalluri, R. (2002) Determinants of Vascular Permeability in the Kidney Glomerulus. J. Biol. Chem. 277, 31154-31162.
40. Jais, J. P., Knebelmann, B., Giatras, I., De Marchi, M., Rizzoni, G., Renieri, A., Weber, M., Gross, O., Netzer, K. O., Flinter, F., Pirson, Y., Verellen, C., Wieslander, J., Persson, U., Tryggvason, K., Martin, P., Hertz, J. M., Schroder, C., Sanak, M., Krejcova, S., Carvalho, M. F., Saus, J., Antignac, C., Smeets, H., and Gubler, M. C. (2000) X-Linked Alport Syndrome: Natural History in 195 Families and Genotype- Phenotype Correlations in Males. J. Am. Soc. Nephrol. 11, 649-657.
41. 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, A. O., Conti, M., Fasciolo, F., Arrondel, C., Heidet, L., Renieri, A., and De Marchi, M. (2002) COL4A3/COL4A4 Mutations: From Familial Hematuria to Autosomal-Dominant Or Recessive Alport Syndrome. Kidney Int. 61, 1947-1956.
42. Thorner, P. S. (2007) Alport Syndrome and Thin Basement Membrane Nephropathy. Nephron Clin. Pract. 106, c82-8.
43. Pierides, A., Voskarides, K., Athanasiou, Y., Ioannou, K., Damianou, L., Arsali, M., Zavros, M., Pierides, M., Vargemezis, V., Patsias, C., Zouvani, I., Elia, A., Kyriacou, K., and Deltas, C. (2009) Clinico-Pathological Correlations in 127 Patients in 11 Large Pedigrees, Segregating One of Three Heterozygous Mutations in the COL4A3/ COL4A4 Genes Associated with Familial Haematuria and Significant Late Progression to Proteinuria and Chronic Kidney Disease from Focal Segmental Glomerulosclerosis. Nephrol. Dial. Transplant. 24, 2721-2729.
44. Gubler, M. C., Knebelmann, B., Beziau, A., Broyer, M., Pirson, Y., Haddoum, F., Kleppel, M. M., and Antignac, C. (1995) Autosomal Recessive Alport Syndrome: Immunohistochemical Study of Type IV Collagen Chain Distribution. Kidney Int. 47, 1142-1147.
45.Zheng, K., Thorner, P. S., Marrano, P., Baumal, R., and McInnes, R. R. (1994) Canine X Chromosome-Linked Hereditary Nephritis: A Genetic Model for Human X-Linked Hereditary Nephritis Resulting from a Single Base Mutation in the Gene Encoding the Alpha 5 Chain of Collagen Type IV. Proc. Natl. Acad. Sci. U. S. A. 91, 3989-3993.
46. Lees, G. E., Helman, R. G., Kashtan, C. E., Michael, A. F., Homco, L. D., Millichamp, N. J., Camacho, Z. T., Templeton, J. W., Ninomiya, Y., Sado, Y., Naito, I., and Kim, Y. (1999) New Form of X-Linked Dominant Hereditary Nephritis in Dogs. Am. J. Vet. Res. 60, 373-383.
47. Cosgrove, D., Meehan, D. T., Grunkemeyer, J. A., Kornak, J. M., Sayers, R., Hunter, W. J., and Samuelson, G. C. (1996) Collagen COL4A3 Knockout: A Mouse Model for Autosomal Alport Syndrome. Genes Dev. 10, 2981-2992.
48. Cosgrove, D., Samuelson, G., Meehan, D. T., Miller, C., McGee, J., Walsh, E. J., and Siegel, M. (1998) Ultrastructural, Physiological, and Molecular Defects in the Inner Ear of a Gene-Knockout Mouse Model for Autosomal Alport Syndrome. Hear. Res. 121, 84-98.
49. Rheault, M. N., Kren, S. M., Thielen, B. K., Mesa, H. A., Crosson, J. T., Thomas, W., Sado, Y., Kashtan, C. E., and Segal, Y. (2004) Mouse Model of X-Linked Alport Syndrome. J. Am. Soc. Nephrol. 15, 1466-1474.
50. Lu, W., Phillips, C. L., Killen, P. D., Hlaing, T., Harrison, W. R., Elder, F. F., Miner, J. H., Overbeek, P. A., and Meisler, M. H. (1999) Insertional Mutation of the Collagen Genes Col4a3 and Col4a4 in a Mouse Model of Alport Syndrome. Genomics. 61, 113-124.
51. Andrews, K. L., Mudd, J. L., Li, C., and Miner, J. H. (2002) Quantitative Trait Loci Influence Renal Disease Progression in a Mouse Model of Alport Syndrome. Am. J. Pathol. 160, 721-730.
52. Kang, J. S., Wang, X. P., Miner, J. H., Morello, R., Sado, Y., Abrahamson, D. R., and Borza, D. B. (2006) Loss of alpha3/alpha4(IV) Collagen from the Glomerular Basement Membrane Induces a Strain-Dependent Isoform Switch to alpha5alpha6(IV) Collagen Associated with Longer Renal Survival in Col4a3-/- Alport Mice. J. Am. Soc. Nephrol. 17, 1962-1969.
53. Rao, V. H., Meehan, D. T., Delimont, D., Nakajima, M., Wada, T., Gratton, M. A., and Cosgrove, D. (2006) Role for Macrophage Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport Syndrome. Am. J. Pathol. 169, 32-46.
54. Cosgrove, D., Rodgers, K., Meehan, D., Miller, C., Bovard, K., Gilroy, A., Gardner, H., Kotelianski, V., Gotwals, P., Amatucci, A., and Kalluri, R. (2000) Integrin alpha1beta1 and Transforming Growth Factor-beta1 Play Distinct Roles in Alport Glomerular Pathogenesis and Serve as Dual Targets for Metabolic Therapy. Am. J. Pathol. 157, 1649-1659.
55. Rao, V. H., Lees, G. E., Kashtan, C. E., Nemori, R., Singh, R. K., Meehan, D. T., Rodgers, K., Berridge, B. R., Bhattacharya, G., and Cosgrove, D. (2003) Increased Expression of MMP-2, MMP-9 (Type IV collagenases/gelatinases), and MT1-MMP in Canine X-Linked Alport Syndrome (XLAS). Kidney Int. 63, 1736-1748.
56. Sterk, L. M., de Melker, A. A., Kramer, D., Kuikman, I., Chand, A., Claessen, N., Weening, J. J., and Sonnenberg, A. (1998) Glomerular Extracellular Matrix Components and Integrins. Cell Adhes. Commun. 5, 177-192.
57. Sachs, N., Kreft, M., van den Bergh Weerman, M. A., Beynon, A. J., Peters, T. A., Weening, J. J., and Sonnenberg, A. (2006) Kidney Failure in Mice Lacking the Tetraspanin CD151. J. Cell Biol. 175, 33-39.
58. Chen, X., Moeckel, G., Morrow, J. D., Cosgrove, D., Harris, R. C., Fogo, A. B., Zent, R., and Pozzi, A. (2004) Lack of Integrin alpha1beta1 Leads to Severe Glomerulosclerosis After Glomerular Injury. Am. J. Pathol. 165, 617-630.
59. Jin, D. K., Fish, A. J., Wayner, E. A., Mauer, M., Setty, S., Tsilibary, E., and Kim, Y. (1996) Distribution of Integrin Subunits in Human Diabetic Kidneys. J. Am. Soc. Nephrol. 7, 2636-2645.
60. Vogel, W., Gish, G. D., Alves, F., and Pawson, T. (1997) The Discoidin Domain Receptor Tyrosine Kinases are Activated by Collagen. Mol. Cell. 1, 13-23.
61. Gross, O., Beirowski, B., Harvey, S. J., McFadden, C., Chen, D., Tam, S., Thorner, P. S., Smyth, N., Addicks, K., Bloch, W., Ninomiya, Y., Sado, Y., Weber, M., and Vogel, W. F. (2004) DDR1-Deficient Mice show Localized Subepithelial GBM Thickening with Focal Loss of Slit Diaphragms and Proteinuria. Kidney Int. 66, 102-111.
62. Gould, D. B., Phalan, F. C., Breedveld, G. J., van Mil, S. E., Smith, R. S., Schimenti, J. C., Aguglia, U., van der Knaap, M. S., Heutink, P., and John, S. W. (2005) Mutations in Col4a1 Cause Perinatal Cerebral Hemorrhage and Porencephaly. Science. 308, 1167-1171.
63. Saus, J., Wieslander, J., Langeveld, J. P., Quinones, S., and Hudson, B. G. (1988) Identification of the Goodpasture Antigen as the Alpha 3(IV) Chain of Collagen IV. J. Biol. Chem. 263, 13374-13380.
64. Altincicek, B., Berisha, A., Mukherjee, K., Spengler, B., Rompp, A., and Vilcinskas, A. (2009) Identification of Collagen IV Derived danger/alarm Signals in Insect Immunity by nanoLC-FTICR MS. Biol. Chem.
65. Kamphaus, G. D., Colorado, P. C., Panka, D. J., Hopfer, H., Ramchandran, R., Torre, A., Maeshima, Y., Mier, J. W., Sukhatme, V. P., and Kalluri, R. (2000) Canstatin, a Novel Matrix-Derived Inhibitor of Angiogenesis and Tumor Growth. J. Biol. Chem. 275, 1209-1215.
66. Morello, R., Zhou, G., Dreyer, S. D., Harvey, S. J., Ninomiya, Y., Thorner, P. S., Miner, J. H., Cole, W., Winterpacht, A., Zabel, B., Oberg, K. C., and Lee, B. (2001) Regulation of Glomerular Basement Membrane Collagen Expression by LMX1B Contributes to Renal Disease in Nail Patella Syndrome. Nat. Genet. 27, 205-208.
67. Bernal, D., Quinones, S., and Saus, J. (1993) The Human mRNA Encoding the Goodpasture Antigen is Alternatively Spliced. J. Biol. Chem. 268, 12090-12094.
68. Feng, L., Xia, Y., and Wilson, C. B. (1994) 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.
69. Cosgrove, D., Kalluri, R., Miner, J. H., Segal, Y., and Borza, D. B. (2007) Choosing a Mouse Model to Study the Molecular Pathobiology of Alport Glomerulonephritis. Kidney Int. 71, 615-618.
70. Koera, K., Nakamura, K., Nakao, K., Miyoshi, J., Toyoshima, K., Hatta, T., Otani, H., Aiba, A., and Katsuki, M. (1997) K-Ras is Essential for the Development of the Mouse Embryo. Oncogene. 15, 1151-1159.
71. Johnson, L., Greenbaum, D., Cichowski, K., Mercer, K., Murphy, E., Schmitt, E., Bronson, R. T., Umanoff, H., Edelmann, W., Kucherlapati, R., and Jacks, T. (1997) K-Ras is an Essential Gene in the Mouse with Partial Functional Overlap with N-Ras. Genes Dev. 11, 2468-2481.
72. Suzuki, Y., Miura, H., Tanemura, A., Kobayashi, K., Kondoh, G., Sano, S., Ozawa, K., Inui, S., Nakata, A., Takagi, T., Tohyama, M., Yoshikawa, K., and Itami, S. (2002) Targeted Disruption of LIG-1 Gene Results in Psoriasiform Epidermal Hyperplasia. FEBS Lett. 521, 67-71.
73. Bloom, A. J., Miller, B. R., Sanes, J. R., and DiAntonio, A. (2007) The Requirement for Phr1 in CNS Axon Tract Formation Reveals the Corticostriatal Boundary as a Choice Point for Cortical Axons. Genes Dev. 21, 2593-2606.
74. Zhang, X., and Firestein, S. (2002) The Olfactory Receptor Gene Superfamily of the Mouse. Nat. Neurosci. 5, 124-133.
75. Schoor, M., Schuster-Gossler, K., Roopenian, D., and Gossler, A. (1999) Skeletal Dysplasias, Growth Retardation, Reduced Postnatal Survival, and Impaired Fertility in Mice Lacking the SNF2/SWI2 Family Member ETL1. Mech. Dev. 85, 73-83.
76. Patel, S., Kartasova, T., and Segre, J. A. (2003) Mouse Sprr Locus: A Tandem Array of Coordinately Regulated Genes. Mamm. Genome. 14, 140-148.
77. Higashi, Y., Moribe, H., Takagi, T., Sekido, R., Kawakami, K., Kikutani, H., and Kondoh, H. (1997) Impairment of T Cell Development in deltaEF1 Mutant Mice. J. Exp. Med. 185, 1467-1479.
78. Takagi, T., Moribe, H., Kondoh, H., and Higashi, Y. (1998) DeltaEF1, a Zinc Finger and Homeodomain Transcription Factor, is Required for Skeleton Patterning in Multiple Lineages. Development. 125, 21-31.
79. Krafchak, C. M., Pawar, H., Moroi, S. E., Sugar, A., Lichter, P. R., Mackey, D. A., Mian, S., Nairus, T., Elner, V., Schteingart, M. T., Downs, C. A., Kijek, T. G., Johnson, J. M., Trager, E. H., Rozsa, F. W., Mandal, M. N., Epstein, M. P., Vollrath, D., Ayyagari, R., Boehnke, M., and Richards, J. E. (2005) Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells. Am. J. Hum. Genet. 77, 694-708.
80. Colville, D. J., and Savige, J. (1997) Alport Syndrome. A Review of the Ocular Manifestations. Ophthalmic Genet. 18, 161-173.
81. Bower, K. S., Edwards, J. D., Wagner, M. E., Ward, T. P., and Hidayat, A. (2009) Novel Corneal Phenotype in a Patient with Alport Syndrome. Cornea. 28, 599-606.
82. Firtina, Z., Danysh, B. P., Bai, X., Gould, D. B., Kobayashi, T., and Duncan, M. K. (2009) Abnormal Expression of Collagen IV in Lens Activates the Unfolded Protein Response Resulting in Cataract. J. Biol. Chem.
|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Carrie N. Arnold and Bruce Beutler|
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