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COL11A2
collagen type XI alpha 2 chain
The COL11A2 gene provides instructions for making a vital component of type XI collagen, a protein crucial for the structure and strength of cartilage and other connective tissues throughout the body. COL11A2 encodes the pro-alpha2(XI) chain of type XI collagen, a complex protein essential for maintaining the integrity of cartilage, bone, and inner ear structures.
COL11A2 is located on the short (p) arm of chromosome 6, at band 6p21.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The COL11A2 gene directs the production of one of the protein chains that constitute type XI collagen. This collagen type is a crucial structural component of various connective tissues, particularly significant in cartilage, the flexible tissue that underpins joints and forms parts of the developing skeleton. The pro-alpha2(XI) chain, encoded by COL11A2, combines with two other collagen chains to assemble the triple-stranded procollagen molecule, which subsequently forms mature collagen fibrils.
Type XI collagen is integral to the mechanical properties of cartilage, imparting both structure and strength. It is also found in the inner ear and the nucleus pulposus, which is the central part of spinal discs. Pathogenic variants within COL11A2 can disrupt the normal assembly and function of type XI collagen, leading to a range of inherited disorders primarily affecting skeletal development and hearing.
What the gene does
The COL11A2 gene carries the genetic instructions for the pro-alpha2(XI) chain, a subunit of type XI collagen. Collagens are a family of proteins that form the primary components of the extracellular matrix, offering structural support and strength to the body's connective tissues. Type XI collagen is predominantly found in cartilage, where it plays a key role in its development and maintenance.
Initially, three procollagen chains-specifically one pro-alpha2(XI) chain, a pro-alpha1(XI) chain, and a pro-alpha1(II) chain-come together to form a rope-like procollagen molecule. This precursor then undergoes enzymatic processing to yield mature collagen. These mature collagen molecules subsequently align to form long, thin fibrils, establishing stable cross-links within the extracellular matrix to create robust type XI collagen fibres. Beyond its direct structural contribution, type XI collagen, via its pro-alpha2(XI) chain, also helps regulate the spacing and diameter of type II collagen fibrils, which are essential for the normal architecture of mature cartilage. Disruptions to this intricate process due to COL11A2 variants can therefore have widespread effects on connective tissue integrity.
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Chromosome location
The COL11A2 gene is located on the short arm of chromosome 6, at position 6p21.32. This chromosomal designation specifies the gene's position within the human genome. The gene provides instructions for synthesising a protein approximately 1736 amino acids in length.
Protein structure
The COL11A2 protein, known as collagen type XI alpha 2 chain, is composed of several distinct domains and regions. Key structural features include a Laminin G-like domain (amino acids 57-228) and a series of collagen-like domains: Collagen-like 1 (amino acids 399-447), Collagen-like 2 (amino acids 487-545), Collagen-like 3 (amino acids 546-590), Collagen-like 4 (amino acids 805-862), Collagen-like 5 (amino acids 863-899), Collagen-like 6 (amino acids 1099-1156), Collagen-like 7 (amino acids 1157-1172), and Collagen-like 8 (amino acids 1441-1499).
The protein also features several Nonhelical regions (e.g., amino acids 215-486) and extensive Disordered regions (e.g., amino acids 227-303, 330-465, 485-1538). A critical Triple-helical region (amino acids 487-1500) facilitates the characteristic collagen triple helix formation, and a C-terminal Fibrillar collagen NC1 domain (amino acids 1541-1735) is also present, which is important for fibril assembly.
Key variants
Variants within the COL11A2 gene can disrupt the normal production or function of the pro-alpha2(XI) collagen chain. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. Depending on their nature and location, such variants can impair the formation of stable type XI collagen, affect its interaction with other collagen types, or lead to its reduced presence in tissues. This can result in a range of health conditions, particularly those affecting connective tissues like cartilage and bone.
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.1019dup | p.Pro340_Glu341insTer | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1297C>T | p.Arg433Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Otospondylomegaepiphyseal dysplasia, autosomal dominant |
c.1606C>T | p.Arg536Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1672C>T | p.Arg558Ter | Pathogenic | ★★☆☆ | Otospondylomegaepiphyseal dysplasia, autosomal recessive |
c.2158C>T | p.Arg720Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Monogenic hearing loss |
c.2763del | p.Gly922fs | Pathogenic | ★★☆☆ | COL11A2-related disorder |
c.3181C>T | p.Arg1061Ter | Pathogenic/Likely pathogenic | ★★☆☆ | COL11A2-related disorder |
c.3329dup | p.Gly1111fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fibrochondrogenesis 2 |
c.3545dup | p.Gly1183fs | Pathogenic/Likely pathogenic | ★★☆☆ | COL11A2-related disorder |
c.3666del | p.Ile1223fs | Pathogenic/Likely pathogenic | ★★☆☆ | COL11A2-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 COL11A2 gene are associated with a group of inherited conditions primarily characterised by skeletal abnormalities and hearing loss. These conditions include fibrochondrogenesis type 2, otospondylomegaepiphyseal dysplasia (OSMED), Weissenbacher-Zweymüller syndrome, and Stickler syndrome. While they share some overlapping features, they vary in severity and specific clinical manifestations. These are typically autosomal recessive conditions, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop the condition. The severity of the condition often depends on the specific genetic variant and its impact on collagen function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic COL11A2 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 COL11A2 gene is listed on several Green RAG (Red, Amber, Green) rated panels within the NHS Genomic Medicine Service's PanelApp, indicating strong evidence for its association with specific conditions. It is included on panels for Clefting, DDG2P (developmental disorders), Foetal anomalies (R21), Monogenic hearing loss (R67), Skeletal dysplasia (R104), and Stickler syndrome (R45).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Currently, there are no specific lifestyle modifications established for COL11A2 variants. General connective tissue health principles may be relevant, but individuals should discuss any concerns with their healthcare provider.
Supplement considerations
There is no conclusive evidence that any specific supplements prevent or modify COL11A2-related conditions. Anyone considering supplements should discuss this with their healthcare provider first.
Frequently asked questions
What is the main function of the COL11A2 gene?
The COL11A2 gene provides instructions for making the pro-alpha2(XI) chain, a component of type XI collagen. This collagen is crucial for providing structural support and strength to cartilage, bone, and other connective tissues throughout the body.
What types of conditions are associated with COL11A2 variants?
Variants in COL11A2 are primarily associated with inherited conditions affecting skeletal development and hearing. These include Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED), Weissenbacher-Zweymüller syndrome, and fibrochondrogenesis type 2.
How are COL11A2-related conditions inherited?
Conditions associated with COL11A2 variants are typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic variant, one from each parent, to be affected by the condition.
References
- Chakchouk I, Grati M, Bademci G. Novel mutations confirm that COL11A2 is responsible for autosomal recessive non-syndromic hearing loss DFNB53. Molecular genetics and genomics : MGG. 2015. PMID: 25633957
- Tompson SW, Faqeih EA, Ala-Kokko L. Dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2. American journal of medical genetics. Part A. 2012. PMID: 22246659
- Ryder JJ, Garrison K, Song F. Genetic associations in peripheral joint osteoarthritis and spinal degenerative disease: a systematic review. Annals of the rheumatic diseases. 2008. PMID: 17720722
- Harel T, Rabinowitz R, Hendler N. COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED). American journal of medical genetics. Part A. 2005. PMID: 15558753
- Jakkula E, Melkoniemi M, Kiviranta I. The role of sequence variations within the genes encoding collagen II, IX and XI in non-syndromic, early-onset osteoarthritis. Osteoarthritis and cartilage. 2005. PMID: 15922184
- Chen W, Kahrizi K, Meyer NC. Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus. Journal of medical genetics. 2005. PMID: 16033917
- De Leenheer EM, Kunst HH, McGuirt WT. Autosomal dominant inherited hearing impairment caused by a missense mutation in COL11A2 (DFNA13). Archives of otolaryngology--head & neck surgery. 2001. PMID: 11177008
- Melkoniemi M, Brunner HG, Manouvrier S. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. American journal of human genetics. 2000. PMID: 10677296
- McGuirt WT, Prasad SD, Griffith AJ. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nature genetics. 1999. PMID: 10581026
- Pihlajamaa T, Prockop DJ, Faber J. Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). American journal of medical genetics. 1998. PMID: 9805126