Affinage

COL4A6

Collagen alpha-6(IV) chain · UniProt Q14031

Length
1691 aa
Mass
163.8 kDa
Annotated
2026-06-09
27 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COL4A6 encodes the alpha6(IV) type IV collagen chain, a basement membrane structural component whose expression is governed by a bidirectional promoter shared head-to-head with COL4A5 on chromosome Xq22 (PMID:7972123). This shared regulatory region drives tissue-specific transcription from two alternative COL4A6 promoters and contains a bidirectional positive regulatory element that enables co-expression of both chains in keratinocytes and other cell types but is inactive in podocytes, which selectively transcribe COL4A5 (PMID:7972123, PMID:11096082); growth factors including TGF-beta, EGF, VEGF, and PDGF further partition expression in a cell-type-specific manner, enhancing alpha6(IV) in tubular epithelial cells while enhancing alpha5(IV) in glomerular cells (PMID:15598179). The alpha6(IV) chain assembles through its NC1 domain and deposits into select basement membranes—Bowman's capsule and distal tubules but notably not the glomerular basement membrane, as well as skin, smooth muscle, and esophageal smooth muscle—while co-localizing with alpha5(IV) (PMID:7657706, PMID:20951201). Two distinct disease mechanisms arise from this gene: contiguous deletions removing the 5' ends and shared bidirectional promoter of both COL4A5 and COL4A6 cause diffuse leiomyomatosis through loss of both chains in esophageal smooth muscle, with deletion breakpoints clustering in COL4A6 intron 2 and arising via topoisomerase- and homologous-recombination-mediated rearrangement of transposed elements (PMID:9463311, PMID:20951201, PMID:28275241); separately, missense and splicing variants in COL4A6 cause X-linked nonsyndromic congenital hearing loss (PMID:23714752, PMID:33840813, PMID:41092388). Because Col4a6 knockout mice develop neither hearing loss nor cochlear malformation despite alpha6(IV) distribution throughout cochlear basement membranes, the hearing-loss mechanism is attributed to dominant-negative disruption of the heterotrimer by aberrant alpha6(IV) chains rather than simple loss of function (PMID:33848312). Genetic epistasis in Col4a3/Col4a6 double-knockout mice shows alpha6(IV) is dispensable for autosomal recessive Alport syndrome progression (PMID:27377778).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Established the genomic architecture underlying COL4A6 regulation by showing it is arranged head-to-head with COL4A5 and driven by a shared bidirectional promoter with two tissue-specific alternative start sites.

    Evidence Genomic sequencing, promoter analysis, and RT-PCR across tissues

    PMID:7972123

    Open questions at the time
    • Did not define the cis-elements conferring tissue specificity
    • Functional consequence of the two transcript isoforms unresolved
  2. 1995 High

    Defined the alpha6(IV) protein product and its restricted basement-membrane distribution, distinguishing it from alpha5(IV) by its absence from the glomerular basement membrane.

    Evidence Chain-specific monoclonal antibodies, Western blot, and immunofluorescence across human tissues

    PMID:7657706

    Open questions at the time
    • Heterotrimer stoichiometry not directly resolved
    • Functional role in each basement membrane not tested
  3. 1995 High

    Resolved the full gene structure including dual alternative first exons, the 7S, collagenous COL1, and NC1 domains, providing the framework for interpreting downstream mutations.

    Evidence Genomic library screening and exon/intron mapping

    PMID:7592929

    Open questions at the time
    • Did not assign functional roles to individual domains
  4. 1998 High

    Linked contiguous deletions removing both COL4A5 and COL4A6 5' regions to diffuse leiomyomatosis with Alport syndrome and implicated topoisomerase-mediated recombination, explaining a co-deletion disease mechanism.

    Evidence Breakpoint sequencing, homology analysis, and immunohistochemistry in DL/AS families

    PMID:9463311

    Open questions at the time
    • Did not establish how loss of both chains drives smooth muscle overgrowth
  5. 2000 High

    Dissected the bidirectional promoter to show distinct minimal promoters and a shared positive regulatory element that permits co-expression in some cell types but not podocytes, explaining cell-type-selective chain expression.

    Evidence Reporter assays, RNase protection, gel shift, and DNase I footprinting in cell lines

    PMID:11096082

    Open questions at the time
    • Trans-acting factors binding the element not identified
  6. 2005 High

    Showed the bidirectional promoter responds to growth factors in a cell-type-specific manner, partitioning alpha5(IV) versus alpha6(IV) induction between glomerular and tubular cells.

    Evidence Bidirectional reporter constructs with growth factor stimulation across renal cell types

    PMID:15598179

    Open questions at the time
    • Signal transduction pathways linking growth factors to the promoter not defined
    • Single lab
  7. 2010 Medium

    Demonstrated that promoter deletion causes clonal esophageal smooth muscle overgrowth, connecting the genetic lesion to a defined tumorigenic clonal expansion.

    Evidence Chain-specific immunohistochemistry and androgen receptor CAG-repeat X-inactivation clonality analysis

    PMID:20951201

    Open questions at the time
    • Mechanism by which collagen chain loss triggers clonal growth unknown
    • Single lab
  8. 2013 Medium

    Identified COL4A6 missense mutation as a cause of X-linked nonsyndromic hearing loss and established inner-ear expression, defining a new disease association distinct from Alport syndrome.

    Evidence NGS with segregation, zebrafish in situ hybridization, mouse inner-ear immunostaining

    PMID:23714752

    Open questions at the time
    • Mechanism by which the missense allele disrupts function not established
    • Single family
  9. 2016 Medium

    Tested whether alpha6(IV) compensates in autosomal recessive Alport syndrome and showed via genetic epistasis it is dispensable, ruling out a major compensatory GBM role.

    Evidence Col4a3/Col4a6 double-knockout mice with renal function and survival analysis

    PMID:27377778

    Open questions at the time
    • Does not address alpha6(IV) function in non-renal basement membranes
    • Single lab
  10. 2021 Medium

    Reconciled the human-mouse discrepancy by showing Col4a6 knockout mice have normal hearing, indicating the human hearing-loss mutation acts through a dominant-negative mechanism rather than loss of function.

    Evidence Col4a6 knockout mice with ABR, micro-CT, histology, and immunohistochemistry

    PMID:33848312

    Open questions at the time
    • Dominant-negative mechanism inferred, not biochemically demonstrated
    • Single lab
  11. 2021 Medium

    Expanded the pathogenic mutational spectrum for hearing loss by demonstrating a splice-site variant causes exon 15 skipping.

    Evidence In vitro minigene splicing assay

    PMID:33840813

    Open questions at the time
    • Effect on protein assembly not tested
    • Single method
  12. 2026 Medium

    Further extended the hearing-loss spectrum to a synonymous variant causing partial exon skipping and reconfirmed conserved otic-vesicle expression, strengthening the developmental role.

    Evidence Exome/genome sequencing, RNA splicing analysis, zebrafish spatiotemporal expression, structural modeling

    PMID:41092388

    Open questions at the time
    • Functional impact of structural model on heterotrimer not validated
    • Single lab
  13. 2020 Low

    Implicated COL4A6 in cancer cell behavior, with knockdown activating p-FAK/MMP-9 signaling to promote prostate cancer invasion and migration.

    Evidence siRNA knockdown with wound healing, transwell invasion, Western blot, and immunofluorescence

    PMID:32551898

    Open questions at the time
    • Pathway assignment lacks direct biochemical validation
    • Single knockdown experiment, no in vivo validation
  14. 2026 Low

    Implicated CAF-derived COL4A6 in gastric cancer progression through CAF activation and induction of epithelial-mesenchymal transition.

    Evidence Single-cell sequencing, CAF cultures, alpha-SMA/FAP and stress-fiber readouts, EMT assays

    PMID:41735371

    Open questions at the time
    • No reconstitution or in vivo validation
    • Mechanism linking secreted collagen to CAF activation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical basis of the inferred dominant-negative heterotrimer disruption in hearing loss, and the trans-acting factors that read the bidirectional promoter to achieve cell-type-specific chain expression, remain undefined.
  • No structural or biochemical demonstration of mutant heterotrimer disruption
  • Transcription factors binding the bidirectional regulatory element unidentified
  • Functional role of alpha6(IV) in each specific basement membrane untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
COL4A5

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 COL4A6 and COL4A5 are arranged head-to-head on chromosome Xq22 and share a common bidirectional promoter region; COL4A6 is transcribed from two alternative promoters in a tissue-specific manner, with one transcript (from exon 1') abundant in placenta and another (from exon 1) more frequent in kidney and lung. Genomic sequencing, 5' flanking sequence analysis, reverse transcription-PCR across tissue types Proceedings of the National Academy of Sciences of the United States of America High 7972123
1995 The alpha6(IV) chain (COL4A6 protein product) is present as 27-kD monomers and associated dimers of the NC1 domain; it localizes to basement membranes of Bowman's capsules and distal tubules in adult kidney but is absent from the glomerular basement membrane, whereas alpha5(IV) is present in the GBM. Both chains co-localize in skin, smooth muscle cells, and adipocytes but are absent or minimal in cardiac muscle and hepatic sinusoidal endothelial cells. Peptide-specific monoclonal antibody generation, Western blotting, immunofluorescence staining across multiple human tissues The Journal of cell biology High 7657706
1995 The COL4A6 gene spans >200 kb, contains 46 exons, with exons 1' and 1 encoding two alternative 5'-UTRs and distinct signal peptide N-termini, exons 2-7 encoding the 7S domain, exons 7-42 encoding the collagenous COL1 domain with Gly-X-Y repeats, and exons 43-45 encoding the NC1 domain. The exon size pattern is highly homologous to COL4A2. Genomic library screening, lambda phage clone characterization, exon/intron mapping, restriction analysis The Journal of biological chemistry High 7592929
1998 Deletions spanning the 5' ends of both COL4A5 and COL4A6 cause diffuse leiomyomatosis (DL) in association with Alport syndrome; the COL4A6 breakpoints in DL/AS cases are clustered within intron 2 of COL4A6. Breakpoint sequences share homology with topoisomerase I and II consensus sequences, implicating topoisomerase-mediated recombination in deletion formation. Immunohistochemical analysis confirmed absence of alpha5(IV) and alpha6(IV) chains in basement membranes of affected smooth muscle tumor tissue. Breakpoint sequence characterization, DNA sequence homology analysis, immunohistochemistry with chain-specific antibodies, somatic mosaicism analysis American journal of human genetics High 9463311
2000 The minimal promoters for COL4A5 and COL4A6 are functionally distinct, residing within 100 bp of their respective transcription start sites. A bidirectional positive regulatory element exists between the two genes that functions in multiple cell types but not in glomerular visceral epithelial cells, which selectively transcribe COL4A5. This element enables co-expression of both genes in keratinocytes but not in podocytes. Transient transfection with reporter gene constructs, RNase protection assays, gel shift assays, DNase I footprinting The Journal of biological chemistry High 11096082
2005 The bifunctional promoter between COL4A5 and COL4A6 regulates their expression in a cell-type-specific manner in response to growth factors. TGF-beta, EGF, VEGF, and PDGF significantly enhance expression from the alpha5(IV) gene in glomerular endothelial cells and mesangial cells but not from the alpha6(IV) gene; conversely, in tubular epithelial cells, these growth factors enhance expression from the alpha6(IV) gene but not the alpha5(IV) gene. Cloning of mouse bifunctional promoter into bidirectional reporter construct (CAT/Luciferase), transfection into glomerular endothelial cells, mesangial cells, and tubular epithelial cells, growth factor stimulation assays The Biochemical journal High 15598179
2010 Alpha5(IV) and alpha6(IV) chains are specifically expressed in esophageal smooth muscle basement membranes within the gastrointestinal tract. Deletion of COL4A5-COL4A6 promoters leads to clonal overgrowth of esophageal smooth muscle cells, demonstrated by CAG repeat analysis of the androgen receptor gene showing X-inactivation on the non-affected allele in leiomyoma cells. Immunohistochemistry with chain-specific antibodies across gastrointestinal tract, CAG repeat analysis of androgen receptor gene for clonal X-inactivation analysis Matrix biology : journal of the International Society for Matrix Biology Medium 20951201
2013 A missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6 causes X-linked nonsyndromic congenital hearing loss without Alport syndrome features. Expression of the COL4A6 homolog was confirmed in the zebrafish otic vesicle by in situ hybridization and in murine inner ear by immunostaining, establishing a role for COL4A6 in inner ear development and function. Next-generation sequencing, Sanger sequencing for segregation, in situ hybridization in zebrafish, immunostaining in mouse inner ear European journal of human genetics : EJHG Medium 23714752
2016 COL4A6 is dispensable for autosomal recessive Alport syndrome: mice lacking both alpha3(IV) and alpha6(IV) chains showed no significant difference in renal function or survival compared to Col4a3 single knockout mice, indicating alpha6(IV) induction in the GBM in autosomal recessive Alport syndrome does not play a major compensatory role. Generation of Col4a3/Col4a6 double knockout mice, renal function measurement, survival analysis, immunostaining Scientific reports Medium 27377778
2017 AS-DL deletions arise predominantly through homologous recombination involving transposed elements (long and short interspersed repeats, DNA transposons, LTR retrotransposons) at sequences homologous between COL4A5 and COL4A6. Eight of nine deletion alleles involved such homologous sequences. The occurrence of leiomyomatosis requires inactivation of both COL4A5 and COL4A6, as all deletions involved the bidirectional promoter region. Breakpoint characterization by PCR and sequencing in five AS-DL patients, sequence homology analysis for transposed elements Journal of human genetics Medium 28275241
2021 Col4a6 knockout mice do not develop hearing loss or cochlear malformation, in contrast to humans with the COL4A6 p.Gly591Ser missense mutation who do. Alpha6(IV) chain is distributed throughout cochlear subepithelial basement membranes in mice. This discrepancy indicates the hearing loss mechanism is likely due to dominant-negative effects of the aberrant alpha6(IV) chain or the alpha5-alpha6-alpha5(IV) heterotrimer, rather than simple loss of function. Col4a6 knockout mouse generation, auditory brainstem response (click-evoked ABR), micro-computed tomography, histology, immunohistochemistry PloS one Medium 33848312
2021 A splicing variant in COL4A6 (c.951+1G>C) causes skipping of exon 15, demonstrated by in vitro minigene splicing assay, establishing a pathogenic mechanism for X-linked nonsyndromic hearing loss. In vitro minigene splicing assay European journal of human genetics : EJHG Medium 33840813
2020 Knockdown of COL4A6 in prostate cancer cells activates the p-FAK/MMP-9 signaling pathway, promoting cell invasion and migration as measured by wound healing and transwell assays. COL4A6 protein localizes extracellularly in prostate cancer cells. siRNA knockdown, wound healing assay, cell invasion transwell assay, Western blot, immunofluorescence staining Genetic testing and molecular biomarkers Low 32551898
2026 A synonymous COL4A6 variant (c.1767G>A, p.Pro589=) causes partial exon skipping, demonstrated by RNA studies, establishing it as pathogenic for X-linked nonsyndromic hearing loss. Structural modeling of missense variant p.Gly494Arg predicts impact on protein structure. Zebrafish spatial and temporal expression analysis confirmed col4a6 expression in the otic vesicle and developing ear from 1 to 5 days post-fertilization. Exome/genome sequencing, RNA splicing analysis, zebrafish expression analysis (spatial/temporal), structural modeling QJM : monthly journal of the Association of Physicians Medium 41092388
2026 COL4A6 produced by cancer-associated fibroblasts (CAFs) promotes tumor progression and stromal remodeling in gastric cancer by inducing CAF activation (upregulation of alpha-SMA and FAP, stress fiber remodeling) and promoting epithelial-mesenchymal transition (EMT) in gastric cancer cells. Single-cell sequencing, CAF-enriched fibroblast cultures, functional experiments measuring alpha-SMA/FAP upregulation and stress fiber remodeling, EMT assays in cancer cells Scientific reports Low 41735371

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Differential expression of two basement membrane collagen genes, COL4A6 and COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies. The Journal of cell biology 239 7657706
1994 The genes COL4A5 and COL4A6, coding for basement membrane collagen chains alpha 5(IV) and alpha 6(IV), are located head-to-head in close proximity on human chromosome Xq22 and COL4A6 is transcribed from two alternative promoters. Proceedings of the National Academy of Sciences of the United States of America 69 7972123
2013 Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6. European journal of human genetics : EJHG 50 23714752
1996 Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome. Journal of the American Society of Nephrology : JASN 42 8738805
1998 Topoisomerase I and II consensus sequences in a 17-kb deletion junction of the COL4A5 and COL4A6 genes and immunohistochemical analysis of esophageal leiomyomatosis associated with Alport syndrome. American journal of human genetics 40 9463311
1997 Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis-Alport syndrome (DL-AS) locus define the DL critical region. Cytogenetics and cell genetics 34 9465897
1998 Somatic deletion of the 5' ends of both the COL4A5 and COL4A6 genes in a sporadic leiomyoma of the esophagus. The American journal of pathology 29 9502408
1995 Isolation and structure of the COL4A6 gene encoding the human alpha 6(IV) collagen chain and comparison with other type IV collagen genes. The Journal of biological chemistry 27 7592929
2002 Alport syndrome associated with diffuse leiomyomatosis: COL4A5-COL4A6 deletion associated with a mild form of Alport nephropathy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 24 11773466
2020 Downregulation of Collagen COL4A6 Is Associated with Prostate Cancer Progression and Metastasis. Genetic testing and molecular biomarkers 23 32551898
2017 Characterization of contiguous gene deletions in COL4A6 and COL4A5 in Alport syndrome-diffuse leiomyomatosis. Journal of human genetics 20 28275241
2005 Bifunctional promoter of type IV collagen COL4A5 and COL4A6 genes regulates the expression of alpha5 and alpha6 chains in a distinct cell-specific fashion. The Biochemical journal 20 15598179
1994 Deletion spanning the 5' ends of both the COL4A5 and COL4A6 genes in a patient with Alport's syndrome and leiomyomatosis. Human mutation 19 7833948
1996 Structure of the human type IV collagen COL4A6 gene, which is mutated in Alport syndrome-associated leiomyomatosis. Genomics 18 8661006
1995 YAC contigs mapping the human COL4A5 and COL4A6 genes and DXS118 within Xq21.3-q22. Genomics 17 7607673
2016 COL4A6 is dispensable for autosomal recessive Alport syndrome. Scientific reports 14 27377778
2013 Deletion of the 5'exons of COL4A6 is not needed for the development of diffuse leiomyomatosis in patients with Alport syndrome. Journal of medical genetics 13 23958657
2000 Regulation of the paired type IV collagen genes COL4A5 and COL4A6. Role of the proximal promoter region. The Journal of biological chemistry 13 11096082
2021 Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications. European journal of human genetics : EJHG 10 33840813
2021 Clinical Manifestations of Alport Syndrome-Diffuse Leiomyomatosis Patients With Contiguous Gene Deletions in COL4A6 and COL4A5. Frontiers in medicine 9 34778325
2015 Chinese family with diffuse oesophageal leiomyomatosis: a new COL4A5/COL4A6 deletion and a case of gonosomal mosaicism. BMC medical genetics 9 26179878
2010 Clonal overgrowth of esophageal smooth muscle cells in diffuse leiomyomatosis-Alport syndrome caused by partial deletion in COL4A5 and COL4A6 genes. Matrix biology : journal of the International Society for Matrix Biology 9 20951201
2018 Missense mutations in COL4A5 or COL4A6 genes may cause cerebrovascular fibromuscular dysplasia: Case report and literature review. Medicine 8 30045277
2021 Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation. PloS one 6 33848312
2026 Uncovering dual molecular diagnoses in families with complex phenotypes through structural and clinical studies of novel COL4A6 variants. QJM : monthly journal of the Association of Physicians 0 41092388
2026 CAF-enriched COL4A6 promotes gastric cancer progression and stromal remodeling despite an inverse association in bulk transcriptomes. Scientific reports 0 41735371
2026 Temporal Transcriptomics Leads From Discovery to in Vivo Validation: COL4A3/COL4A6/ COL4A5 and ITGA8 as Novel Arthrofibrosis Biomarkers in Post-traumatic Joint Contracture. Dose-response : a publication of International Hormesis Society 0 41743075

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