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COL4A4
collagen type IV alpha 4 chain
The COL4A4 gene provides instructions for making one of the alpha chains of type IV collagen, a crucial structural component of basement membranes found in many tissues, particularly the kidneys, inner ear, and eyes. COL4A4 is responsible for producing the alpha-4 chain of type IV collagen.
COL4A4 is located on the long (q) arm of chromosome 2, at band 2q36.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The COL4A4 gene, or collagen type IV alpha 4 chain, is a gene that encodes a subunit of type IV collagen. This specific alpha-4 chain combines with other collagen chains (alpha-3 and alpha-5) to form a complex protein network known as alpha345(IV) collagen molecules. These networks are vital structural components of basement membranes.
Basement membranes are thin, supportive layers that separate and provide structural integrity to cells across various tissues. In particular, the alpha345(IV) collagen networks play a significant role in the integrity of basement membranes in organs like the kidneys, inner ear, and eyes.
What the gene does
The primary function of the COL4A4 gene is to provide the genetic blueprint for the alpha-4 subunit of type IV collagen. This alpha-4 chain is crucial for the assembly of alpha345(IV) collagen molecules, which then interlink to create complex protein networks. These networks are fundamental to the structure and function of basement membranes.
Basement membranes act as selective filters and support structures for cells. Their integrity is particularly important in the kidneys, where they form part of the filtration barrier, and in the inner ear and eyes, where they contribute to normal function. Proper formation of these collagen networks, facilitated by the COL4A4 gene product, is therefore essential for healthy tissue architecture and function in these organs.
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Chromosome location
The COL4A4 gene is situated on chromosome 2 at position 2q36.3. This means it is located on the long arm (q) of chromosome 2, specifically within region 36, band 3. The precise number of exons for this gene is not commonly cited as a primary structural feature in basic gene descriptions.
Protein structure
The COL4A4 protein is 1690 amino acids in length and features several notable regions and motifs. It includes a 7S domain located at amino acids 39-64 and a prominent Triple-helical region spanning amino acids 65-1459, which is characteristic of collagen proteins. Several Disordered regions are present, for example, from amino acids 61-173, 187-258, 369-390, 405-451, and 469-1457. Additionally, multiple Cell attachment sites are identified, including at amino acids 94-96, 145-147, 189-191, 310-312, 724-726, 785-787, 989-991, and 1212-1214.
Key variants
Genetic variations, also known as variants, within the COL4A4 gene can alter the production or function of the alpha-4 collagen chain. These changes may lead to impaired formation of the essential type IV collagen networks in basement membranes. Variants can range from single amino acid changes to larger deletions or insertions, impacting the protein's stability or its ability to interact with other collagen chains.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1283dup | p.Pro428_Asp429insTer | Pathogenic/Likely pathogenic | ★★☆☆ | COL4A4-related disorder |
c.1308dup | p.Lys437fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Alport syndrome |
c.1352G>A | p.Gly451Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Alport syndrome |
c.1505dup | p.Gly503fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Alport syndrome |
c.1777G>T | p.Gly593Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Alport syndrome |
c.1803+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Alport syndrome |
c.1943G>A | p.Gly648Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Alport syndrome |
c.2115dup | p.Lys706Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Alport syndrome |
c.2892_2893insC | p.Met965fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Alport syndrome |
c.3787C>T | p.Gln1263Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Alport syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the COL4A4 gene are associated with several inherited conditions, primarily affecting the kidneys. One notable condition is Alport syndrome (autosomal recessive), which is characterised by kidney disease, hearing loss, and eye abnormalities. Another condition linked to COL4A4 variants is Thin basement membrane nephropathy, which typically presents with blood in the urine (haematuria) but often with no other significant symptoms of kidney disease.
- Alport syndrome (autosomal recessive)
- Thin basement membrane nephropathy Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic COL4A4 variants typically follow ar/ad inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The COL4A4 gene is recognised within the NHS Genomic Medicine Service due to its association with inherited kidney disorders. It is listed as 'green' on several NHS Genomic Medicine Service national panels via PanelApp, including DDG2P, Haematuria (R194), Proteinuric renal disease (R195), and Unexplained kidney failure in young people, indicating strong evidence for its clinical utility in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the COL4A4 gene?
The COL4A4 gene provides instructions for making the alpha-4 chain of type IV collagen. This protein is a vital component of basement membranes, which are crucial supportive structures in various tissues, especially the kidneys, inner ear, and eyes.
What health conditions are associated with variants in COL4A4?
Variants in the COL4A4 gene are primarily associated with inherited kidney conditions. These include Alport syndrome (autosomal recessive), which affects kidneys, hearing, and eyes, and Thin basement membrane nephropathy, typically causing blood in the urine.
How does COL4A4 contribute to kidney function?
The protein produced by COL4A4 helps form alpha345(IV) collagen networks that are integral to the basement membranes in the kidneys. These membranes are essential for the kidney's filtration process, helping to remove waste while retaining important substances in the blood.
References
- Slajpah M, Gorinsek B, Berginc G. Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney international. 2007. PMID: 17396119
- Gregory MC. The clinical features of thin basement membrane nephropathy. Seminars in nephrology. 2005. PMID: 15880323
- Rana K, Wang YY, Buzza M. The genetics of thin basement membrane nephropathy. Seminars in nephrology. 2005. PMID: 15880327
- Pescucci C, Mari F, Longo I. Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene. Kidney international. 2004. PMID: 15086897
- Buzza M, Dagher H, Wang YY. Mutations in the COL4A4 gene in thin basement membrane disease. Kidney international. 2003. PMID: 12631110
- Gross O, Netzer KO, Lambrecht R. Novel COL4A4 splice defect and in-frame deletion in a large consanguine family as a genetic link between benign familial haematuria and autosomal Alport syndrome. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2003. PMID: 12748344
- Tazón Vega B, Badenas C, Ars E. Autosomal recessive Alport's syndrome and benign familial hematuria are collagen type IV diseases. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2003. PMID: 14582039
- Longo I, Porcedda P, Mari F. COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney international. 2002. PMID: 12028435
- Kashtan CE. Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. Medicine. 1999. PMID: 10499074
- Adam MP, Bick S, Mirzaa GM. Alport Syndrome. 1993. PMID: 20301386