Collagen, type II, alpha 1

COL2A1
Available structures
PDBOrtholog search: PDBeRCSB
Identifiers
AliasesCOL2A1, AOM, COL11A3, Cartilage collagen, ANFH, STL1, collagen type II alpha 1, collagen type II alpha 1 chain, SEDC, Collagen II
External IDsOMIM: 120140; MGI: 88452; HomoloGene: 55607; GeneCards: COL2A1; OMA:COL2A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1280

12824

Ensembl

ENSG00000139219

ENSMUSG00000022483

UniProt

P02458

P28481

RefSeq (mRNA)

NM_001844NM_033150

NM_001113515NM_031163

RefSeq (protein)

NP_001835NP_149162

NP_001106987NP_112440

Location (UCSC)Chr 12: 47.97 – 48 MbChr 15: 97.87 – 97.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital), also known as COL2A1, is a humangene that provides instructions for the production of the pro-alpha1(II) chain of type II collagen.

Gene

The COL2A1 gene is located on the long (q) arm of chromosome 12 between positions 13.11 and 13.2, from base pair 46,653,017 to base pair 46,684,527. The expression of COL2A1 is regulated by SOX-9 and retrotransposon gag-like-3 gene RTL3 in chondrocytes.[5]

There are two transcripts identified for this gene.[6]

Function

This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye.[6]

Type II collagen, which adds structure and strength to connective tissues, is found primarily in cartilage, the jelly-like substance that fills the eyeball (the vitreous), the inner ear, and the center portion of the discs between the vertebrae in the spine (nucleus pulposus). Three pro-alpha1(II) chains twist together to form a triple-stranded, ropelike procollagen molecule. These procollagen molecules must be processed by enzymes in the cell. Once these molecules are processed, they leave the cell and arrange themselves into long, thin fibrils that cross-link to one another in the spaces around cells. The cross-linkages result in the formation of very strong mature type II collagen fibers.[6]

Clinical significance

Mutations in the COL2A1 gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome, and spondyloepimetaphyseal dysplasia Strudwick type.[6][7][8] In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia.[6]

Achondrogenesis type 2

Several kinds of mutations in the COL2A1 gene are responsible for Achondrogenesis type 2. These include missing pieces of the gene, substitution of the amino acidglycine with another amino acid, or changes that result in truncated proteins. All these mutations disrupt the production of mature type II collagen, affecting tissues rich in this collagen.

Platyspondylic lethal skeletal dysplasia, Torrance type

Fewer than 10 COL2A1 mutations have been identified in people with Platyspondylic lethal skeletal dysplasia, Torrance type. Most result in a single amino acid change in the pro-alpha1(II) chain, producing an abnormal chain that cannot be incorporated into collagen fibers. This leads to reduced collagen production and skeletal abnormalities such as short limbs, small chest, flattened vertebrae, and short fingers and toes.

Hypochondrogenesis

Hypochondrogenesis is caused by various COL2A1 mutations, including deletions, glycine substitutions, and truncations. These interfere with the formation of mature, triple-stranded type II collagen molecules, affecting collagen-rich tissues.

Kniest dysplasia

Most mutations responsible for Kniest dysplasia result in abnormally short pro-alpha1(II) collagen chains that combine with normal-length chains, producing shorter-than-normal collagen molecules. This results in the characteristic features of Kniest dysplasia.

Spondyloepimetaphyseal dysplasia

All known COL2A1 mutations in Spondyloepimetaphyseal dysplasia, Strudwick type replace glycine with another amino acid in the pro-alpha1(II) chain, disrupting the formation of stable, triple-stranded collagen molecules.

Spondyloepiphyseal dysplasia congenita is caused by several types of COL2A1 mutations, including incorrect amino acid substitutions and truncated pro-alpha1(II) chains, impairing the formation of mature collagen molecules.[9]

In Spondyloperipheral dysplasia, COL2A1 mutations produce a truncated pro-alpha1(II) chain that cannot be incorporated into collagen fibers. The abnormal chains accumulate in cartilage cells, disrupting bone development and resulting in flattened vertebrae and short digits.

Stickler syndrome

Several COL2A1 mutations cause Stickler syndrome, often leading to the production of a truncated protein that cannot be incorporated into collagen fibers. Many mutations introduce premature stop signals, resulting in a 50% reduction of pro-alpha1(II) collagen chains and underproduction of type II collagen in cartilage.[10]

Osteoarthritis risk

Variations in the COL2A1 gene may increase susceptibility to osteoarthritis in some individuals. These variations alter amino acids in the pro-alpha1(II) chain, potentially affecting collagen fiber integrity in joint cartilage and contributing to degenerative joint disease.

References

  1. ^ abcGRCh38: Ensembl release 89: ENSG00000139219 – Ensembl, May 2017
  2. ^ abcGRCm38: Ensembl release 89: ENSMUSG00000022483 – Ensembl, May 2017
  3. ^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Ball HC, Ansari MY, Ahmad N, Novak K, Haqqi TM (November 2021). "A retrotransposon gag-like-3 gene RTL3 and SOX-9 co-regulate the expression of COL2A1 in chondrocytes". Connective Tissue Research. 62 (6): 615–628. doi:10.1080/03008207.2020.1828380. ISSN 1607-8438. PMC 8404968. PMID 33043724.
  6. ^ abcde"Entrez Gene: COL2A1 collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital)".
  7. ^Deng H, Huang X, Yuan L (2016). "Molecular genetics of the COL2A1-related disorders". Mutation Research. Reviews in Mutation Research. 768: 1–13. Bibcode:2016MRRMR.768....1D. doi:10.1016/j.mrrev.2016.02.003. PMID 27234559.
  8. ^Zhang B, Zhang Y, Wu N, Li J, Liu H, Wang J (March 2020). "Integrated analysis of COL2A1 variant data and classification of type II collagenopathies". Clinical Genetics. 97 (3): 383–395. doi:10.1111/cge.13680. PMID 31758797.
  9. ^Nenna R, Turchetti A, Mastrogiorgio G, Midulla F (2019). "COL2A1 Gene Mutations: Mechanisms of Spondyloepiphyseal Dysplasia Congenita". The Application of Clinical Genetics. 12: 235–238. doi:10.2147/TACG.S197205. PMC 6900288. PMID 31824186.
  10. ^Higuchi Y, Hasegawa K, Yamashita M, Tanaka H, Tsukahara H (August 2017). "A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature". Journal of Medical Case Reports. 11 (1): 237. doi:10.1186/s13256-017-1396-y. PMC 5574094. PMID 28841907.

Further reading

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