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COL6A2
collagen type VI alpha 2 chain
The COL6A2 gene provides instructions for making a key component of type VI collagen, a crucial protein for structural support in muscles and connective tissues. COL6A2 produces the alpha-2(VI) chain of type VI collagen, which is vital for the extracellular matrix surrounding cells.
COL6A2 is located on the long (q) arm of chromosome 21, at band 21q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The COL6A2 gene encodes one of the essential chains of type VI collagen, a complex protein found in the extracellular matrix. This matrix is the intricate network surrounding cells that provides physical support and plays a role in cell stability and growth. Collagen type VI is particularly important in skeletal muscles and various connective tissues throughout the body, including skin and joints.
What the gene does
The COL6A2 gene directs the synthesis of the alpha-2(VI) chain, which combines with other collagen chains to form complete type VI collagen molecules. This collagen is a flexible protein located in the extracellular matrix, offering structural support to tissues. It helps link thin, sheet-like structures known as basement membranes to adjacent cells, which is critical for tissue organisation. The integrity of type VI collagen is vital for the proper function of muscles and connective tissues, ensuring their strength and flexibility.
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Chromosome location
The COL6A2 gene is situated on the long arm of chromosome 21 at position 22.3, denoted as 21q22.3. This specific location defines its genomic address within the human genome.
Protein structure
The COL6A2 protein is 1019 amino acids long and features several distinct regions and domains. It contains two significant nonhelical regions, one spanning amino acids 21-256 and another from 591-1019. Within these nonhelical segments are several VWFA domains: VWFA 1 (amino acids 46-234), VWFA 2 (amino acids 615-805), and VWFA 3 (amino acids 833-1014). A central triple-helical region, extending from amino acids 257-590, includes a disordered segment from 257-588. Additionally, multiple cell attachment sites, which are specific motifs, are located at amino acids 366-368, 426-428, 489-491, 498-500, and 539-541.
Key variants
Variants within the COL6A2 gene can alter the structure or function of the alpha-2(VI) collagen chain, potentially disrupting the stability and integrity of type VI collagen. These changes can lead to a range of muscle and connective tissue disorders. Most frequently, pathogenic variants involve alterations to single amino acids within the protein sequence.
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.1053+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.1180-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.1817-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.1821_1822del | p.Cys607_Glu608delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.1990C>T | p.Gln664Ter | Pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.2099G>A | p.Gly700Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1B |
c.736-1G>A | - | Pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.784G>T | p.Gly262Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.802G>A | p.Gly268Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Bethlem myopathy 1A |
c.900+1G>T | - | Pathogenic | ★★☆☆ | COL6A2-related disorder |
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 COL6A2 gene are associated with inherited conditions primarily affecting muscles and connective tissues. These include Bethlem myopathy, which typically presents with muscle weakness and joint contractures, and Ullrich congenital muscular dystrophy, a more severe form characterised by significant muscle weakness and joint hyperlaxity alongside contractures. These conditions are part of a broader group known as collagen VI-related dystrophies.
- Bethlem myopathy
- Ullrich congenital muscular dystrophy Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic COL6A2 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
The COL6A2 gene is included in several UK NHS national genomic testing panels. It is covered by panels for conditions such as Arthrogryposis (R83), Congenital muscular dystrophy (R79), Congenital myopathy (R81), and Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies (R82). It is also part of the DDG2P and Foetal anomalies (R21) panels, as well as the Ehlers Danlos syndrome with a likely monogenic cause (R101) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the COL6A2 gene?
The COL6A2 gene provides instructions for making a specific component, the alpha-2(VI) chain, of type VI collagen. This collagen is a crucial protein found in the extracellular matrix, which provides structural support to cells and tissues, particularly in muscles and connective tissues.
What conditions are associated with COL6A2 gene variants?
Variants in the COL6A2 gene are primarily associated with a group of muscle and connective tissue disorders. These include Bethlem myopathy, characterised by muscle weakness and joint contractures, and the more severe Ullrich congenital muscular dystrophy.
How does COL6A2 relate to collagen?
COL6A2 directly contributes to the formation of type VI collagen. The protein produced by COL6A2, the alpha-2(VI) chain, combines with other collagen chains to assemble the complete type VI collagen molecule, which is essential for maintaining tissue structure and integrity.
References
- Bushby KM, Collins J, Hicks D. Collagen type VI myopathies. Advances in experimental medicine and biology. 2014. PMID: 24443028
- Bönnemann CG. The collagen VI-related myopathies: muscle meets its matrix. Nature reviews. Neurology. 2011. PMID: 21691338
- Allamand V, Briñas L, Richard P. ColVI myopathies: where do we stand, where do we go? Skeletal muscle. 2011. PMID: 21943391
- Baker NL, Mörgelin M, Pace RA. Molecular consequences of dominant Bethlem myopathy collagen VI mutations. Annals of neurology. 2007. PMID: 17886299
- Baker NL, Mörgelin M, Peat R. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Human molecular genetics. 2005. PMID: 15563506