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COL4A3
collagen type IV alpha 3 chain
The COL4A3 gene provides instructions for making a crucial component of type IV collagen, essential for the structural integrity of basement membranes in various tissues. COL4A3 encodes the alpha3(IV) chain of collagen IV, a protein vital for forming complex networks in basement membranes.
COL4A3 is located on the long (q) arm of chromosome 2, at band 2q36.3. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
The COL4A3 gene provides the genetic blueprint for the alpha3(IV) chain, one of the protein building blocks that form collagen IV. Collagen IV is a fundamental component of basement membranes, which are thin, sheet-like structures acting as scaffolding to separate and support cells in numerous tissues throughout the body. These collagen IV networks are particularly important for the proper functioning of the kidneys, inner ear, and eyes.
What the gene does
The primary role of the COL4A3 gene is to direct the production of the alpha3(IV) chain, which combines with alpha4(IV) and alpha5(IV) chains to create alpha345(IV) collagen molecules. These specific collagen molecules then assemble into intricate networks that constitute a significant portion of basement membranes. In the kidneys, these basement membranes are critical for filtering waste from the blood. In the inner ear, they are involved in hearing, and in the eye, they contribute to vision. Dysfunction of these collagen networks can impair the structural and filtering capabilities of these vital organs.
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Chromosome location
The COL4A3 gene is situated on chromosome 2, specifically at position 2q36.3. This location denotes its address on the long arm of chromosome 2. The gene spans a region of DNA that contains the instructions for synthesising the 1670 amino acid long collagen type IV alpha 3 chain protein.
Protein structure
The COL4A3 protein, comprising 1670 amino acids, features several distinct regions and motifs. It includes a 7S domain (amino acids 29-42) and a prominent Triple-helical region (amino acids 43-1438). Disordered regions are found at amino acids 49-78, 167-469, and 502-1442, suggesting flexibility in these areas. The protein also contains multiple Cell attachment sites located at amino acids 791-793, 996-998, 1154-1156, 1306-1308, 1345-1347, and 1432-1434. A specific Epitope recognised by Goodpasture antibodies spans amino acids 1427-1444. The Collagen IV NC1 domain is present at amino acids 1445-1669, which also contains regions required for the anti-angiogenic activity of tumstatin (amino acids 1479-1557) and the anti-tumour cell activity of tumstatin (amino acids 1610-1628).
Key variants
Variants within the COL4A3 gene can impact the production or function of the alpha3(IV) collagen chain, leading to various health conditions. Many of these genetic changes involve alterations to single amino acids in critical regions where the collagen chains interact. Other variants can significantly reduce or prevent the formation of the alpha3(IV) chain entirely. The clinical consequences depend on the specific variant and its effect on protein function.
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 |
|---|---|---|---|---|
GRCh37/hg19 2q36.3(chr2:228099222-228185228)x1 | - | Pathogenic | ★☆☆☆ | not specified |
g.(?_228029443)_(228176586_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228102664)_(228176586_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228113139)_(228118910_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228117992)_(228124613_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228120722)_(228121132_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228128486)_(228128670_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228137645)_(228137853_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228153846)_(228160052_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_228162380)_(228163538_?)del | - | Pathogenic | ★☆☆☆ | not provided |
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
Pathogenic variants in the COL4A3 gene are associated with several inherited conditions, primarily affecting the kidneys. The most well-known is Alport syndrome (autosomal recessive), a progressive kidney disease often accompanied by hearing loss and eye abnormalities. Variants in one copy of the COL4A3 gene can also cause Thin basement membrane nephropathy, which typically presents as blood in the urine (haematuria) without other significant symptoms of kidney disease. This condition rarely progresses to kidney failure.
- Alport syndrome (autosomal recessive)
- Alport syndrome (X-linked)
- Thin basement membrane nephropathy Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic COL4A3 variants typically follow autosomal recessive 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
COL4A3 is an important gene within the UK's genomic healthcare system. It is recognised on several NHS Genomic Medicine Service national test directories through PanelApp, including DDG2P, Haematuria (R194), Proteinuric renal disease (R195), and Unexplained kidney failure in young people. This indicates its clinical relevance for diagnosing and managing related conditions within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the COL4A3 gene?
The COL4A3 gene provides instructions for making the alpha3(IV) chain of collagen IV. This protein chain is crucial for forming complex networks that give structural support to basement membranes, particularly in the kidneys, inner ear, and eyes.
Which conditions are associated with COL4A3 variants?
Variants in the COL4A3 gene are primarily associated with kidney conditions such as Alport syndrome (autosomal recessive) and Thin basement membrane nephropathy. Alport syndrome can lead to progressive kidney disease, hearing loss, and eye abnormalities, while Thin basement membrane nephropathy typically causes haematuria.
Is COL4A3 included in UK genetic testing panels?
Yes, COL4A3 is listed on several NHS Genomic Medicine Service national test directories via PanelApp. These include panels for conditions such as Haematuria, Proteinuric renal disease, and Unexplained kidney failure in young people, highlighting its clinical significance in the UK.
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
- Wang YY, Rana K, Tonna S. COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). Kidney international. 2004. PMID: 14871398
- 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
- Adam MP, Bick S, Mirzaa GM. Alport Syndrome. 1993. PMID: 20301386