Disease relevance of COL4A3

• The autosomal recessive form of Alport syndrome is caused by mutations in the COL4A3 and COL4A4 genes, located at 2q35-37 [1].
• COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome [2].
• Autosomal recessive Alport syndrome is a progressive hematuric glomerulonephritis characterized by glomerular basement membrane abnormalities and associated with mutations in either the COL4A3 or the COL4A4 gene, which encode the alpha3 and alpha4 type IV collagen chains, respectively [3].
• Affected humans and COL4A3-deficient mice develop glomerulosclerosis and progressive renal fibrosis in the presence of interstitial macrophages, but their contribution to disease progression is under debate [4].
• Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis [5].

High impact information on COL4A3

• Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome [6].
• We present here linkage of benign familial hematuria with the COL4A3 and COL4A4 genes at 2q35-37 (Zmax = 3.58 at theta = 0.0) [7].
• These findings suggest that a major subgroup of patients with hereditary glomerulonephritis have biochemical abnormalities of the GBM involving Goodpasture antigen and that MCA-P1 is useful in the differential diagnosis of children with haematuria [8].
• Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells [9].
• To determine whether the alpha 3(IV) gene (COL4A3) may be mutated in Alport syndrome, we localized it, by somatic cell hybrid analysis and in situ hybridization of metaphase chromosomes, to chromosome 2q35-2q37 [10].

Chemical compound and disease context of COL4A3

• In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot [11].
• Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome [12].

Biological context of COL4A3

• To investigate, in vivo, the regulation of the expression, assembly, and function of the alpha3alpha4alpha5(IV) protomer, we have generated a yeast artificial chromosome transgenic line of mice carrying the human COL4A3-COL4A4 locus [13].
• Autosomal dominant AS has been mapped to chromosome 2 in the region of COL4A3 and COL4A4 [14].
• RESULTS: We identified seven previously undescribed COL4A3 mutations: in two genetic compounds and three heterozygotes, and one in COL4A4 [2].
• Twenty-one unrelated children with persistent familial hematuria as well as their families were studied for segregation of hematuria with haplotypes at the COL4A3/COL4A4 locus for benign familial hematuria and at the COL4A5 locus for X-linked Alport syndrome [15].
• When screening lymphocyte COL4A3 mRNAs from Alport patients, we found a mutant whose transcripts were disrupted by a 74 bp insertion at the junction of exons IV or V and VI [16].

Anatomical context of COL4A3

• This study examined how often children with persistent familial hematuria were from families where hematuria segregated with the known genetic locus for the condition known as benign familial hematuria or thin basement membrane nephropathy (TBMN) at COL4A3/COL4A4 [15].
• Immunohistochemical analysis using antibodies specific for the basement membrane collagen chains revealed the absence of the COL4A3 and COL4A4 chains throughout the membranous labyrinth [17].
• Treatment with BX471 from weeks 6 to 10 of life improved survival of COL4A3-deficient mice, associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli [4].
• This question was addressed by treating COL4A3-deficient mice with BX471, an antagonist of chemokine receptor 1 (CCR1) that is known to block interstitial leukocyte recruitment [4].
• Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice [18].

Associations of COL4A3 with chemical compounds

• Using the COL4A3 -/- mouse, an animal model for human AS, we evaluated therapy with ramipril in mice [12].
• Characterization of a novel type of serine/threonine kinase that specifically phosphorylates the human goodpasture antigen [19].
• Polyacrylamide gel electrophoresis, enzyme-linked immunosorbent assay, and chemical analysis were used to demonstrate that the collagenase-resistant sequences of type IV collagen contain Goodpasture antigen [20].
• 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 [21].
• On rat and human GBM the patterns obtained with rat autoantibody and autoantibody from a patient with Goodpasture syndrome were similar, suggesting that some of the in vivo bound anti-GBM autoantibodies in HgCl2-induced disease in rat are directed against epitopes which are similar to the Goodpasture antigen of human [22].

Other interactions of COL4A3

• Three of those, COL4A3, COL4A4, and COL4A5, are linked with Alport syndrome (hereditary nephritis) [23].
• The autosomal recessive form is caused by mutation in the COL4A3 gene, which encodes the alpha 3 chain of type IV collagen, or in the COL4A4 gene, which encodes the alpha 4 chain of type IV collagen [24].
• Evidence for selective sweeps is also found in many other regions, including genes known to be associated with disease risk such as DPP10 and COL4A3 [25].
• The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores: -6.1 and -4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage [26].
• However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections [18].

Analytical, diagnostic and therapeutic context of COL4A3

• Northern blot analysis using probes specific for the collagen chains illustrate the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains are unchanged [6].
• COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC) [27].
• DNA was extracted from leukocytes and subjected to genomic tissue typing and sequencing of the COL4A3 gene exons 48-52 [28].
• Molecular cloning of the human Goodpasture antigen demonstrates it to be the alpha 3 chain of type IV collagen [29].
• In addition, evidence for an altered GBM antigenicity came from immunofluorescence studies which showed a reduced or absent binding of anti-GBM autoantibodies or monoclonal antibodies to the "Goodpasture antigen" in some families [30].

References