Affinage

COL4A3

Collagen alpha-3(IV) chain · UniProt Q01955

Length
1670 aa
Mass
161.8 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COL4A3 encodes the α3 chain of type IV collagen, an obligate building block of the α3α4α5(IV) heterotrimeric network that constitutes the mature glomerular basement membrane (GBM) filtration barrier (PMID:8956999, PMID:14507670). Network assembly requires all three chains: knockout of COL4A3 eliminates α3, α4, and α5(IV) from the GBM and produces progressive glomerulonephritis with GBM multilamination and end-stage renal disease, while reintroduction of human α3(IV) restores co-assembly of the heterotrimer and rescues the phenotype (PMID:8956999, PMID:14507670). COL4A3 and the adjacent COL4A4 are arranged head-to-head and share a bidirectional, TATA-less promoter, and both chains are independently required for GBM integrity (PMID:10534397, PMID:9537506); transcription is directly repressed by ZEB1/TCF8 binding E2-box motifs in the promoter, loss of which drives ectopic α3(IV) expression in corneal endothelium (PMID:27537263, PMID:16252232). The chains are deposited specifically by podocytes rather than endothelial cells, identifying the podocyte lineage as the relevant target for genetic correction (PMID:30724107, PMID:31754267). Pathogenic COL4A3 mutations—including splice-altering, frameshift, and missense changes—cause autosomal recessive and dominant Alport syndrome by disrupting heterotrimer assembly and secretion (PMID:7633417, PMID:11044206, PMID:35386907); misfolded mutant α3 chains accumulate in the ER, are cleared by the proteasome, and trigger persistent ER stress that activates the unfolded protein response and the MyD88/p38 MAPK pathway, driving podocyte apoptosis and fibrosis (PMID:25514610, PMID:31306228, PMID:38782199). Downstream, mutation-induced injury proceeds through a NOX4→MMP-2 apoptotic pathway in podocytes (PMID:37705901), while collagen-receptor signalling through integrin α2β1 drives fibrosis progression (PMID:24480069). Disease severity is modulated by compensatory ectopic deposition of α5α6(IV) collagen, which partially substitutes for the absent network and prolongs renal survival (PMID:16769745). Chemical chaperones (TUDCA, 4-PBA) that relieve ER stress and promote mutant chain secretion improve GBM lesions and kidney function, establishing the assembly/secretion defect as a tractable therapeutic target (PMID:38782199, PMID:40484355). Absence of α3(IV) from the GBM also breaks immunological tolerance to the NC1 domain Goodpasture epitope, underlying post-transplant anti-GBM nephritis (PMID:7780062, PMID:7783419, PMID:33774048).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 High

    Established that COL4A3 is required to assemble the α3α4α5(IV) collagen network in the GBM, defining its core in-vivo function and the basis of Alport pathology.

    Evidence COL4A3 knockout mouse analyzed by immunofluorescence, TEM, and Northern blot

    PMID:8956999

    Open questions at the time
    • Did not resolve whether α3/α4/α5 are co-dependent for assembly or whether each is individually required
    • Cell-type source of the chains not addressed
  2. 1998 High

    Mapped the COL4A3/COL4A4 head-to-head genomic arrangement and bidirectional TATA-less promoter, defining the transcriptional architecture controlling both chains.

    Evidence Genomic cloning, RACE, and RNase protection mapping of transcription start sites

    PMID:9537506

    Open questions at the time
    • No trans-acting factors identified at this stage
    • Tissue-specific regulation not addressed
  3. 1999 High

    Showed both α3 and α4 chains are individually required for GBM integrity and that joint loss accelerates disease, confirming non-redundant roles via the shared promoter.

    Evidence Transgenic insertional knockout (OVE250) ablating the shared promoter, with RT-PCR, immunostaining, and EM

    PMID:10534397

    Open questions at the time
    • Insertional deletion removes regulatory elements as well as coding exons, complicating attribution
  4. 2003 High

    Demonstrated by transgenic rescue that providing α3(IV) restores heterotrimer co-assembly and reverses the Alport phenotype, proving defective assembly is the pathogenic mechanism.

    Evidence YAC transgenic rescue in Col4a3-/- mice with immunofluorescence and functional renal readouts

    PMID:14507670

    Open questions at the time
    • Did not define cell-type of expression required for rescue
    • Did not address mutant (vs absent) chain behavior
  5. 2006 High

    Identified compensatory α5α6(IV) deposition as a strain-dependent modifier that partially substitutes for the lost network and prolongs survival, explaining phenotypic variability.

    Evidence Col4a3-/- mice across genetic backgrounds with immunofluorescence and survival analysis

    PMID:16769745

    Open questions at the time
    • Molecular trigger for the isoform switch unknown
    • Human relevance of α5α6 substitution not established here
  6. 2005 Medium

    Linked ZEB1/TCF8 to COL4A3 transcriptional repression, showing that loss of the repressor causes ectopic COL4A3 expression in corneal endothelium (PPCD3).

    Evidence TCF8 mutation analysis, promoter binding-site identification, and IHC of corneal endothelium

    PMID:16252232

    Open questions at the time
    • Direct DNA binding not demonstrated in this study
    • Mechanism inferred from IHC and in silico analysis
  7. 2016 High

    Confirmed ZEB1 as a direct transcriptional repressor of COL4A3 by showing binding to E2-box motifs and repression of promoter activity.

    Evidence EMSA and dual-luciferase reporter assays with ZEB1 overexpression and truncation mutants

    PMID:27537263

    Open questions at the time
    • In-vivo relevance to GBM regulation not tested
    • Other E2-box factors not excluded
  8. 2021 Medium

    Extended transcriptional control of COL4A3 to an epigenetic mechanism in airway epithelium, identifying intronic methylation and ZNF263 binding as regulators of expression.

    Evidence RNA-seq, methylation arrays, ChIP-seq, and ZNF263 siRNA silencing in bronchial epithelium

    PMID:34109240

    Open questions at the time
    • Relevance to renal/GBM COL4A3 expression unclear
    • Single-lab finding in non-renal tissue
  9. 2014 High

    Placed integrin α2β1 collagen-receptor signalling as a driver of fibrosis progression downstream of GBM injury, identifying a modifiable disease pathway.

    Evidence Col4a3-/-/Itga2-/- double-knockout mice with EM, MMP/TIMP profiling, and survival readouts

    PMID:24480069

    Open questions at the time
    • Cell-type mediating integrin signalling not isolated
    • Mechanism connecting integrin to MMP normalization not fully resolved
  10. 2014 Medium

    Began defining how mutant α3 chains cause injury, showing intracellular retention and differential UPR activation in podocytes.

    Evidence Transfection of podocytes with mutant COL4A3 and UPR pathway analysis

    PMID:25514610

    Open questions at the time
    • Single method type in cell culture
    • Causal link from UPR to phenotype severity not demonstrated in vivo
  11. 2019 High

    Established the podocyte lineage as the obligate source of α3(IV) and the relevant target for gene correction, while excluding endothelial cells.

    Evidence Endothelial-specific transgene failure to rescue Col4a3-/- mice; CRISPR/Cas9 reversion in patient urine-derived podocyte-lineage cells

    PMID:30724107 PMID:31754267

    Open questions at the time
    • Long-term functional rescue after CRISPR correction not shown
    • Editing efficiency in vivo not established
  12. 2019 Medium

    Identified the proteasome as the degradation route for misfolded mutant α3 chains and linked their accumulation to ER stress-mediated podocyte apoptosis.

    Evidence Lentiviral expression of truncated COL4A3 in human podocytes with MG132/brefeldin A inhibition and CRISPR KO

    PMID:31306228

    Open questions at the time
    • Single-lab cell-culture system
    • Specific ER stress effectors not delineated
  13. 2020 Medium

    Showed in a knock-in model that mutant and partner chains undergo proteolytic cleavage producing a C-terminal fragment, implicating extracellular processing in pathology.

    Evidence Col4a3 p.Gly1332Glu knock-in mice with Western blot, immunostaining, EM, and MMP-inhibitor inference

    PMID:33718859

    Open questions at the time
    • MMP-9 mediation inferred from fragment size, not directly demonstrated
    • Functional consequence of the fragment unknown
  14. 2021 High

    Resolved hexamer assembly mechanisms structurally and showed bioactive NC1 surface sites converge the pathogenic pathways of Goodpasture's and Alport syndromes.

    Evidence Knock-in mouse with C-terminal appendage, crystallography, and hexamer assembly studies

    PMID:33774048

    Open questions at the time
    • Direct demonstration of autoantibody-triggering in vivo not part of this study
  15. 2023 High

    Defined a NOX4→MMP-2→apoptosis pathway as the downstream effector of COL4A3 mutation-induced podocyte injury, identifying druggable nodes.

    Evidence Mutant human podocytes and p.C1615Y knock-in mice with NOX4 and MMP-2 inhibitors, microarray, and IHC

    PMID:37705901

    Open questions at the time
    • Connection between ER stress and NOX4 induction not fully mapped
    • Generalizability across mutation classes not established
  16. 2024 High

    Linked the secretion defect to a defined ER-stress signalling axis (MyD88/p38 MAPK) and demonstrated pharmacological rescue, establishing ER stress as a therapeutic target.

    Evidence Col4a3 p.Gly799R knock-in mice with RNA-seq, Western blot, immunofluorescence, and TUDCA treatment

    PMID:38782199

    Open questions at the time
    • Whether all mutation classes respond to ER-stress relief unclear
    • Durability of TUDCA benefit not addressed
  17. 2025 High

    Confirmed that chemical-chaperone rescue (4-PBA) enhances mutant chain folding, secretion, and ECM incorporation, reducing GBM lesions and fibrosis.

    Evidence Col4a3 p.Gly1332Glu knock-in mice with EM, histology, and proteasome-inhibition validation in primary podocytes

    PMID:40484355

    Open questions at the time
    • Mutation-class dependence of response not defined
    • Translational dosing/safety not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream ER stress signalling connects to the NOX4→MMP-2 apoptotic axis and to integrin-driven fibrosis, and which mutation classes are amenable to chaperone-based correction, remains to be unified.
  • No single model integrates ER stress, oxidative/MMP, and integrin pathways
  • Predictors of therapeutic responsiveness across mutation types not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0031012 extracellular matrix 3 GO:0005576 extracellular region 2
Pathway
R-HSA-1474244 Extracellular matrix organization 3 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
COL4A4COL4A5DDR1ITGA2ZEB1ZNF263
Complex memberships
α345(IV) NC1 hexamerα3α4α5(IV) collagen heterotrimer

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Knockout of COL4A3 in mice results in absence of the α3, α4, and α5(IV) collagen chains from the glomerular basement membrane (GBM), with persistence of α1 and α2 chains, demonstrating that COL4A3 is required for assembly of the α3α4α5(IV) network in the GBM. Loss causes progressive glomerulonephritis with GBM multilamination, fibronectin/HSPG/laminin-1/entactin accumulation, and end-stage renal disease. COL4A3 knockout mouse; immunofluorescence; transmission electron microscopy; Northern blot Genes & development High 8956999
1999 Deletion of exons 1–12 of Col4a4 together with exons 1–2 of the adjacent Col4a3 and the intergenic promoter abolishes transcription and protein expression of both chains, confirming that the two genes share a bidirectional promoter and that both α3 and α4 chains are individually required for GBM integrity; loss of both accelerates disease onset compared with loss of α3 alone. Transgenic insertional knockout (OVE250 line); FISH mapping; RT-PCR; immunostaining; electron microscopy Genomics High 10534397
1998 COL4A3 and COL4A4 are arranged head-to-head on chromosome 2q36, sharing a bidirectional promoter region enriched in CpG dinucleotides, GC boxes, CTC boxes, and a CCAAT box but lacking a TATA box; transcription start sites for each gene were mapped by RACE and RNase protection assays. Genomic cloning; RACE; RNase protection assay; nucleotide sequence analysis FEBS letters High 9537506
2003 Expression of human COL4A3 (via YAC transgene) in Col4a3-/- mice restores co-assembly of the α3/α4/α5(IV) heterotrimer specifically at sites of human α3(IV) expression, rescues GBM function, and reverses the Alport phenotype. This demonstrates that expression of all three chains is required for network assembly and that defective assembly is the pathogenic mechanism. YAC transgenic rescue in Col4a3-/- mice; immunofluorescence; histology; functional renal assessment The American journal of pathology High 14507670
2006 In Col4a3-/- mice, loss of the α3/α4(IV) chains from the GBM induces ectopic deposition of α5/α6(IV) collagen; the degree of this compensatory isoform switch is strain-dependent (abundant in C57BL/6, near-absent in 129X1/Sv) and correlates with ~46% longer renal survival, revealing a functional substitution capacity of α5α6(IV) for the absent α3α4α5(IV) network. Col4a3-/- mouse on multiple genetic backgrounds; immunofluorescence; survival analysis; X-linked inheritance analysis in F1 crosses Journal of the American Society of Nephrology : JASN High 16769745
1995 A G-to-T transversion in COL4A3 intron V activates a cryptic splice acceptor within an antisense Alu element, causing insertion of a 74-bp Alu-derived sequence into the COL4A3 mRNA, disrupting the open reading frame and causing autosomal recessive Alport syndrome. mRNA screening; RT-PCR; direct sequencing; family segregation analysis Human molecular genetics High 7633417
2000 A COL4A3 splice site mutation causing skipping of exon 21 (in-frame deletion, NC domain intact) produces a COL4A3 chain predicted to be incorporated into the triple helix and exert a dominant-negative effect, establishing the molecular basis for autosomal dominant Alport syndrome. Nested RT-PCR; DHPLC; DNA sequencing; family segregation Kidney international Medium 11044206
1995 A 7-bp deletion in exon 5 of COL4A3 predicts truncation of the α3(IV) chain with loss of 222 amino acids from the carboxy-terminal NC1 domain; the truncated chain is predicted unable to form trimers, and the loss of the Goodpasture epitope (residing in the NC1 domain) is proposed to underlie post-transplant anti-GBM nephritis. PCR amplification and sequencing of COL4A3 exon 5; parental heterozygosity confirmed by sequencing Journal of the American Society of Nephrology : JASN Medium 7780062
1995 Post-transplant alloantibodies in an autosomal recessive Alport patient with a COL4A3 mutation (predicted loss of 85% of the α3(IV) NC1 domain) target primarily the α3(IV) collagen chain, the same epitope targeted in X-linked Alport patients with COL4A5 deletions, demonstrating that absence of α3(IV) from the GBM (whether from failed synthesis or failed assembly) leads to loss of immunological tolerance to the α3(IV) NC1 domain. Recombinant type IV collagen domain binding assays; characterization of alloantibody specificity using GBM constituents Kidney international Medium 7783419
2014 Collagen receptors DDR1 and integrin α2β1 regulate maturation of the GBM. In the Col4a3-/- Alport model, loss of integrin α2β1 (COL4A3-/-/ITGA2-/- double KO) reduces proteinuria, lowers blood urea nitrogen, extends lifespan by ~20%, decreases glomerular and tubulointerstitial matrix deposition, and normalises elevated MMP2/9/12 and TIMP1 levels, demonstrating that integrin α2β1-mediated collagen signalling drives fibrosis progression. Double-knockout mouse model; electron microscopy; MMP/TIMP expression analysis; survival and functional readouts Matrix biology : journal of the International Society for Matrix Biology High 24480069
2014 In cultured podocytes transfected with mutant COL4A3 chains, mutant collagens are retained intracellularly and differentially activate the unfolded protein response (UPR) cascade, implicating ER stress as a modulator of phenotypic severity in COL4A3 nephropathy. Transfection of podocytes with wild-type or mutant COL4A3; UPR pathway analysis PloS one Medium 25514610
2019 COL4A3 expressed specifically in endothelial cells of Col4a3-/- mice (using an inducible endothelial-specific transgene) does not produce detectable collagen α3α4α5(IV) in the GBM and does not rescue the Alport phenotype, establishing that endothelial cells do not express the Col4a3/a4/a5 genes and are not a viable target for gene therapy. Endothelial cell-specific inducible transgenic expression in Col4a3-/- mice; immunofluorescence; phenotype assessment American journal of physiology. Renal physiology High 30724107
2019 A missense mutation in COL4A3 (p.G856Glu) was successfully reverted toward wild type in podocyte-lineage cells isolated from patient urine using CRISPR/Cas9 genome editing (>40% reversion, <15% indels), demonstrating that podocyte-lineage cells are the relevant cellular target for COL4A3 gene correction. CRISPR/Cas9 genome editing; mCherry/GFP reporter system; Sanger sequencing in patient-derived podocyte-lineage cells European journal of human genetics : EJHG Medium 31754267
2019 A COL4A3 frameshift mutation (c.4317delA) causing a truncated NC1 domain induces excessive endoplasmic reticulum stress and ER stress-mediated apoptosis in human podocytes. Proteasomal inhibition (MG132) increases intracellular accumulation of the truncated chain, worsening ER stress and apoptosis, identifying the proteasome as the primary degradation route for the misfolded mutant chain. Lentiviral stable transfection of human podocytes; RT-PCR; Western blot; pharmacological inhibition (MG132, brefeldin A); CRISPR/Cas9 KO podocytes Chinese medical journal Medium 31306228
2021 A COL4A3 variant (8-residue appendage at C-terminus of the α3 subunit of the α345 hexamer) introduced as a knock-in in mice causes GBM abnormalities and proteinuria phenocopying Alport syndrome. Crystallography and assembly studies revealed hexamer mechanisms; bioactive sites on the hexamer surface converge pathogenic pathways of Goodpasture's and Alport syndrome. Knock-in mouse model; crystallography; hexamer assembly studies; immunostaining; functional proteinuria readout The Journal of biological chemistry High 33774048
2020 A knock-in mouse harboring Col4a3 p.Gly1332Glu recapitulates Alport syndrome features. In glomeruli, the mutant α3 chain and the normal α4/α5 chains appear to undergo proteolytic cleavage near the mutation site, producing a ~35 kDa C-terminal fragment, possibly mediated by MMP-9, while tubuli show reduced mutant collagen expression. Knock-in and compound heterozygous mouse models; Western blot; immunostaining; electron microscopy; serum urea/creatinine; MMP inhibitor inference Matrix biology plus Medium 33718859
2021 COL4A3 expression in bronchial epithelium is negatively regulated by intronic DNA methylation (cg11797365); methylation at this site is increased by rhinovirus infection in vitro. ZNF263 binds this intronic region (by ChIP-seq), and ZNF263 silencing reduces COL4A3 expression, identifying an epigenetic/transcriptional mechanism controlling COL4A3 levels in airway epithelium. RNA-sequencing; DNA methylation bead arrays; ChIP-seq with qPCR; siRNA silencing of ZNF263 ERJ open research Medium 34109240
2016 ZEB1 (TCF8) binds to six of nine E2-box motifs in the COL4A3 promoter (demonstrated by EMSA) and overexpression of ZEB1 reduces COL4A3 promoter activity in luciferase reporter assays, establishing ZEB1 as a direct transcriptional repressor of COL4A3. Electrophoretic mobility shift assay (EMSA); dual-luciferase reporter assay; ZEB1 overexpression and truncation mutants Investigative ophthalmology & visual science High 27537263
2005 TCF8 (ZEB1) frameshift/nonsense mutations in PPCD3 families result in ectopic expression of COL4A3 in corneal endothelial cells, demonstrated by immunohistochemistry, and a TCF8 binding site (core plus secondary) was identified in the COL4A3 promoter, establishing TCF8 as a transcriptional repressor of COL4A3 whose loss causes aberrant COL4A3 expression. Mutation analysis; in silico promoter analysis; immunohistochemistry in corneal endothelium American journal of human genetics Medium 16252232
2022 COL4A3 missense/synonymous variants p.(Leu1598Arg) and p.(Thr255Thr) were shown by in vitro minigene assay to alter RNA splicing—p.(Leu1598Arg) eliminates an alternative full-length transcript and p.(Thr255Thr) causes in-frame deletion of exon 13—demonstrating that exonic substitutions can pathogenically disrupt COL4A3 splicing. In vitro minigene splicing assay; Sanger sequencing; clinical segregation Frontiers in medicine Medium 35386907
2024 A knock-in mouse bearing Col4a3 p.Gly799R shows pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers; mutant α3 chains accumulate in the ER and exhibit defective secretion, causing persistent ER stress and activating the MyD88/p38 MAPK pathway. Treatment with TUDCA (ER stress inhibitor) suppresses ER stress, promotes α3 chain secretion, and improves kidney function in vivo. Transgenic knock-in mouse; Western blot; immunofluorescence; RNA-seq; in vitro cell assays; pharmacological TUDCA treatment Kidney international High 38782199
2023 In podocytes and mice harboring COL4A3 p.C1616Y (murine p.C1615Y), microarray and validation experiments show upregulation of NOX4, H2O2, MMP-2, and apoptosis-related genes. NOX4 inhibition abrogates podocyte apoptosis and downregulates MMP-2 in vivo and in vitro; MMP-2 inhibition reduces apoptosis without affecting NOX4, placing COL4A3 mutation-induced podocyte apoptosis in a NOX4→MMP-2→apoptosis pathway. Microarray analysis on patient glomeruli; mutant human podocyte cell line; knock-in mice (p.C1615Y); NOX4 inhibitor (GKT137831) and MMP-2 inhibitor (SB-3CT); Western blot; immunohistochemistry; RT-PCR Kidney international reports High 37705901
2025 Treatment of Col4a3 p.Gly1332Glu knock-in mice with 4-phenylbutyrate (4-PBA) improves secretion of mutant α3 chains and their incorporation into extracellular matrix (likely by enhancing trimer folding), reduces GBM lesions by 54%, decreases fibrosis and glomerulosclerosis, and maintains low proteinuria. In-vitro proteasomal inhibition in cultured podocytes confirmed that misfolded mutant collagen is degraded by the proteasome. Knock-in mouse model; electron microscopy; histology; proteasome inhibitor in primary podocytes; Western blot Kidney international High 40484355
2012 Proteomic analysis of Col4a3-/- glomeruli revealed upregulation of vimentin (~2.5-fold by 2D-DIGE, ~5.4-fold by qRT-PCR) specifically in podocytes, as well as increased integrin α1 in mesangial cells and integrin α3 in podocytes, indicating that loss of the α3α4α5(IV) GBM network alters podocyte cytoskeletal and adhesion-receptor expression. 2D-DIGE proteomics; mass spectrometry; qRT-PCR; quantitative confocal immunofluorescence; Col4a3-/- mouse model PloS one Medium 23236390

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes & development 298 8956999
1994 Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alport syndrome. Human molecular genetics 186 7987301
2002 COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney international 167 12028435
2005 Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. American journal of human genetics 154 16252232
2001 Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. Journal of the American Society of Nephrology : JASN 150 11134255
2013 COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. Journal of the American Society of Nephrology : JASN 134 24052634
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. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 124 19357112
2004 Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney international 112 15086897
2000 Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney international 109 11044206
1997 Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 106 9269635
1995 Splice-mediated insertion of an Alu sequence in the COL4A3 mRNA causing autosomal recessive Alport syndrome. Human molecular genetics 98 7633417
2002 Mutations in theCOL4A4 and COL4A3 genes cause familial benign hematuria. Journal of the American Society of Nephrology : JASN 86 11961012
2020 Prevalence of clinical, pathological and molecular features of glomerular basement membrane nephropathy caused by COL4A3 or COL4A4 mutations: a systematic review. Clinical kidney journal 76 33391746
2009 Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus. Molecular vision 66 20029656
2007 Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney international 58 17396119
2014 Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2beta1 delays kidney fibrosis in COL4A3 knockout mice. Matrix biology : journal of the International Society for Matrix Biology 57 24480069
2014 Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing. PloS one 55 25514610
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. Journal of the American Society of Nephrology : JASN 55 16769745
2004 COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). Kidney international 55 14871398
2014 COL4A3 mutations cause focal segmental glomerulosclerosis. Journal of molecular cell biology 54 25596306
1999 Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome. Genomics 54 10534397
2023 Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice. Journal of the American Society of Nephrology : JASN 51 37428955
2022 Genotype-Phenotype Correlations for Pathogenic COL4A3-COL4A5 Variants in X-Linked, Autosomal Recessive, and Autosomal Dominant Alport Syndrome. Frontiers in medicine 46 35602506
2005 Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome. Human mutation 42 15954103
2019 New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells. European journal of human genetics : EJHG 41 31754267
2003 A human-mouse chimera of the alpha3alpha4alpha5(IV) collagen protomer rescues the renal phenotype in Col4a3-/- Alport mice. The American journal of pathology 40 14507670
1995 Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis. Journal of the American Society of Nephrology : JASN 39 7780062
1998 Two genes, COL4A3 and COL4A4 coding for the human alpha3(IV) and alpha4(IV) collagen chains are arranged head-to-head on chromosome 2q36. FEBS letters 38 9537506
2006 Chronic renal failure and shortened lifespan in COL4A3+/- mice: an animal model for thin basement membrane nephropathy. Journal of the American Society of Nephrology : JASN 34 16775036
2023 The Phenotypic Spectrum of COL4A3 Heterozygotes. Kidney international reports 31 37849993
2019 Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport Syndrome using next generation sequence technique. Molecular genetics & genomic medicine 30 30968591
2008 COL4A3/COL4A4 mutations link familial hematuria and focal segmental glomerulosclerosis. glomerular epithelium destruction via basement membrane thinning? Connective tissue research 28 18661361
2007 Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases. Pediatric nephrology (Berlin, Germany) 28 17216251
1995 A COL4A3 gene mutation and post-transplant anti-alpha 3(IV) collagen alloantibodies in Alport syndrome. Kidney international 26 7783419
2021 Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases. The Journal of biological chemistry 25 33774048
2013 Antifibrotic, nephroprotective effects of paricalcitol versus calcitriol on top of ACE-inhibitor therapy in the COL4A3 knockout mouse model for progressive renal fibrosis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 25 24198271
2008 COL4A3 founder mutations in Greek-Cypriot families with thin basement membrane nephropathy and focal segmental glomerulosclerosis dating from around 18th century. Genetic testing 24 18439107
2014 Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease. BMC nephrology 23 25381091
2018 COL4A3 Gene Variants and Diabetic Kidney Disease in MODY. Clinical journal of the American Society of Nephrology : CJASN 22 30012629
2017 Association of COL4A3 (rs55703767), MMP-9 (rs17576)and TIMP-1 (rs6609533) gene polymorphisms with susceptibility to type 2 diabetes. Biomedical reports 22 28451395
2014 Polymorphism analysis of COL4A3 and COL4A4 genes in Greek patients with keratoconus. Ophthalmic genetics 22 25083577
2024 Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation. Kidney international 20 38782199
2017 Correlation between the COL4A3, MMP-9, and TIMP-1 polymorphisms and risk of keratoconus. Japanese journal of ophthalmology 20 28197741
2017 Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome. PloS one 20 28542346
2019 Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X-linked Alport syndrome. Molecular genetics & genomic medicine 19 30883042
2014 Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families. Clinical genetics 19 25307543
2021 COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy. The European respiratory journal 18 34326188
2019 Endothelial cell-specific collagen type IV-α3 expression does not rescue Alport syndrome in Col4a3-/- mice. American journal of physiology. Renal physiology 18 30724107
2018 Associations of high-altitude polycythemia with polymorphisms in PIK3CD and COL4A3 in Tibetan populations. Human genomics 17 30053909
2012 Upregulated expression of integrin α1 in mesangial cells and integrin α3 and vimentin in podocytes of Col4a3-null (Alport) mice. PloS one 17 23236390
2002 Segregation of experimental autoimmune glomerulonephritis as a complex genetic trait and exclusion of Col4a3 as a candidate gene. Experimental nephrology 16 12381925
2022 Presumed COL4A3/COL4A4 Missense/Synonymous Variants Induce Aberrant Splicing. Frontiers in medicine 15 35386907
2013 A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population. Clinical genetics 15 23927549
2019 Endoplasmic reticulum stress and proteasome pathway involvement in human podocyte injury with a truncated COL4A3 mutation. Chinese medical journal 13 31306228
2010 Novel heterozygous COL4A3 mutation in a family with late-onset ESRD. Pediatric nephrology (Berlin, Germany) 13 20177710
2024 Increased prevalence of kidney cysts in individuals carrying heterozygous COL4A3 or COL4A4 pathogenic variants. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 12 38317457
2020 How to resolve confusion in the clinical setting for the diagnosis of heterozygous COL4A3 or COL4A4 gene variants? Discussion and suggestions from nephrologists. Clinical and experimental nephrology 12 32232700
2007 A novel mutation of COL4A3 presents a different contribution to Alport syndrome and thin basement membrane nephropathy. American journal of nephrology 12 17726307
2021 Differential expression of COL4A3 and collagen in upward and downward progressing types of nasopharyngeal carcinoma. Oncology letters 11 33613712
2014 A new mutation in the COL4A3 gene responsible for autosomal dominant Alport syndrome, which only generates hearing loss in some carriers. European journal of medical genetics 11 25450602
2020 A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome. Matrix biology plus 10 33718859
2013 A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family. Genetic testing and molecular biomarkers 10 23297803
2008 Novel COL4A3 mutations in African American siblings with autosomal recessive Alport syndrome. American journal of kidney diseases : the official journal of the National Kidney Foundation 10 18436078
2004 Patients with Goodpasture's disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen alpha 3 chain. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 10 15199166
2023 COL4A3 Mutation Induced Podocyte Apoptosis by Dysregulation of NADPH Oxidase 4 and MMP-2. Kidney international reports 9 37705901
2022 Heterozygous COL4A3/COL4A4 mutations: the hidden part of the iceberg? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 9 35090027
2022 Col4a3 Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds. International journal of molecular sciences 9 35743114
2023 Abnormal mRNA Splicing Effect of COL4A3 to COL4A5 Unclassified Variants. Kidney international reports 8 37441478
2023 A Deeper Insight into COL4A3, COL4A4, and COL4A5 Variants and Genotype-Phenotype Correlation of a Turkish Cohort with Alport Syndrome. Molecular syndromology 8 38357258
2021 COL4A3 expression in asthmatic epithelium depends on intronic methylation and ZNF263 binding. ERJ open research 8 34109240
2017 Phenotype variability in a large Spanish family with Alport syndrome associated with novel mutations in COL4A3 gene. BMC nephrology 8 29089023
2022 Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco. Molecular biology reports 7 35301649
2025 Chemical chaperone 4-phenylbutyrate treatment alleviates the kidney phenotype in a mouse model of Alport syndrome with a pathogenic variant in Col4a3. Kidney international 6 40484355
2024 Slowly progressive autosomal dominant Alport Syndrome due to COL4A3 splicing variant. European journal of human genetics : EJHG 6 39424670
2019 Possible Digenic Disease in a Caucasian Family with COL4A3 and COL4A5 Mutations. Nephron 6 30661074
2017 Mutation analysis of COL4A3 and COL4A4 genes in a Chinese autosomal-dominant Alport syndrome family. Journal of genetics 6 28674241
2024 Four novel mutations identified in the COL4A3, COL4A4 and COL4A5 genes in 10 families with Alport syndrome. BMC medical genomics 5 38978054
2021 Association of Collagen Gene (COL4A3) rs55703767 Variant With Response to Riboflavin/Ultraviolet A-Induced Collagen Cross-Linking in Female Patients With Keratoconus. Cornea 5 33079919
2020 Compound Mutations of the COL4A3 including a Novel Allele Identified in a Patient with Alport Syndrome. BioMed research international 5 33524082
2020 Heterozygous Urinary Abnormality-Causing Variants of COL4A3 and COL4A4 Affect Severity of Autosomal Recessive Alport Syndrome. Kidney360 5 35369551
2016 Investigating the Molecular Basis of PPCD3: Characterization of ZEB1 Regulation of COL4A3 Expression. Investigative ophthalmology & visual science 5 27537263
2024 Characterization of Ocular Morphology in Col4a3-/- Mice as a Murine Model for Alport Syndrome. Translational vision science & technology 4 39042048
2021 COL1A1, COL4A3, TIMP2 and TGFB1 polymorphisms in cervical insufficiency. Journal of perinatal medicine 4 33550735
2020 Alport syndrome: Proteomic analysis identifies early molecular pathway alterations in Col4a3 knock out mice. Nephrology (Carlton, Vic.) 4 32743880
2024 Integrated Analysis Reveals COL4A3 as a Novel Diagnostic and Therapeutic Target in UV-Related Skin Cutaneous Melanoma. Clinical, cosmetic and investigational dermatology 3 38911338
2021 NPHS2 gene polymorphism aggravates renal damage caused by focal segmental glomerulosclerosis with COL4A3 mutation. Bioscience reports 3 33305316
2020 Successful renal transplantation in a family with a novel mutation in COL4A3 gene and autosomal recessive Alport syndrome. Nephrology (Carlton, Vic.) 3 31925849
2020 Thrombosis risk of Alport syndrome patients: evaluation of cardiological, clinical, biochemical, genetic and possible causes of inherited thrombophilia and identification of a novel COL4A3 variant. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 3 32332277
2019 A Novel Heterozygous Mutation of the COL4A3 Gene Causes a Peculiar Phenotype without Hematuria and Renal Function Impairment in a Chinese Family. Disease markers 3 30881523
2018 The COL4A3 and COL4A4 Digenic Mutations in cis Result in Benign Familial Hematuria in a Large Chinese Family. Cytogenetic and genome research 3 29742505
2025 Pathogenic synonymous variation of the COL4A3 gene causing Alport syndrome comorbid with IgA deposition in a toddler: a case report. BMC nephrology 2 40866801
2024 Case report: A novel compound heterozygous variant in the COL4A3 gene was identified in a patient with autosomal recessive Alport syndrome. Frontiers in genetics 2 39071776
2021 Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants. Annals of human genetics 2 34888854
2017 A case of mild phenotype Alport syndrome caused by COL4A3 mutations. CEN case reports 2 28856578
2014 Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice. Proteome science 2 25525413
2012 Renal transplantations from parents to siblings with autosomal recessive Alport syndrome caused by a rearrangement in an intronic antisense Alu element in the COL4A3 gene led to different outcomes. CEN case reports 2 28509228
2005 Evaluation of canine COL4A3 and COL4A4 as candidates for familial renal disease in the Norwegian elkhound. The Journal of heredity 2 16014809
2025 Effects of a Novel COL4A3 Homozygous/Heterozygous Splicing Mutation on the Mild Phenotype in a Family With Autosomal Recessive Alport Syndrome and a Literature Review. Molecular genetics & genomic medicine 1 39924725
2025 Whole exome sequencing shows novel COL4A3 and COL4A4 variants as causes of Alport syndrome in Rio Grande do Norte, Brazil. BMC genomics 1 40169949
2025 Lithuanian Study on COL4A3 and COL4A4 Genetic Variants in Alport Syndrome: Clinical Characterization of 52 Individuals from 38 Families. International journal of molecular sciences 1 40806767

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