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COL11A2 gene

collagen type XI alpha 2 chain
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Normal Function

The COL11A2 gene provides instructions for making a component of type XI collagen called the pro-alpha2(XI) chain. Collagens are molecules that provide structure and strength to the connective tissues that support the body's muscles, joints, organs, and skin. Type XI collagen is normally found in cartilage, a tough but flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears. Type XI collagen made with the pro-alpha2(XI) chain is also part of the inner ear and the nucleus pulposus, which is the center portion of the discs between the bones of the spine (vertebrae).

Collagens begin as rope-like procollagen molecules that are each made up of three chains. The pro-alpha2(XI) chain combines with two other collagen chains, pro-alpha1(XI) and pro-alpha1(II), to form a triple-stranded procollagen molecule. Then the ropelike procollagen is processed by enzymes to create mature collagen. Mature collagen molecules arrange themselves into long, thin fibrils that form stable interactions (cross-links) with one another in the spaces between cells (the extracellular matrix). The cross-links result in the formation of very strong type XI collagen fibers.

Type XI collagen also helps maintain the spacing and width (diameter) of another type of collagen molecule, type II collagen. Type II collagen is an important component of mature cartilage. The arrangement and size of type II collagen fibrils is essential for the normal structure of these tissues.

Health Conditions Related to Genetic Changes

Fibrochondrogenesis

At least two mutations in the COL11A2 gene have been identified in people with fibrochondrogenesis type 2, a disorder of bone growth characterized by severe skeletal abnormalities and hearing loss. Infants with fibrochondrogenesis type 2 have a very narrow chest that prevents the lungs from developing normally. Most infants with this condition are stillborn or die shortly after birth from respiratory failure, although some have lived into childhood.

The COL11A2 gene mutations that cause fibrochondrogenesis type 2 lead to the production of an abnormal version of the pro-alpha2(XI) chain. When this abnormal chain is incorporated into collagen molecules, it creates defective type XI collagen. The abnormal collagen weakens connective tissues, impairing the formation of bones throughout the skeleton and causing changes in the inner ear that lead to hearing problems.

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Nonsyndromic hearing loss

Mutations in the COL11A2 gene have been identified in people with nonsyndromic hearing loss, which is loss of hearing that is not associated with other signs and symptoms. Mutations in this gene can cause two forms of nonsyndromic hearing loss: DFNA13 and DFNB53.

DFNA13 is inherited in an autosomal dominant pattern, which means only one mutated copy of the COL11A2 gene in each cell is sufficient to cause the condition. This type of hearing loss begins in childhood or adolescence. It is classified as postlingual because it starts after a child learns to speak.

At least two COL11A2 gene mutations have been identified in people with DFNA13. Both of these mutations change a single protein building block (amino acid) in the pro-alpha2(XI) chain of type XI collagen. These mutations are thought to change the structure of type XI collagen, which plays an important role in the structure and function of the inner ear.

DFNB53 is inherited in an autosomal recessive pattern, which means both copies of the COL11A2 gene are mutated in each cell. It is characterized by profound hearing loss that is present before a child learns to speak (prelingual).

At least three mutations in the COL11A2 gene have been found to cause DFNB53. Each of these mutations changes a single amino acid in the pro-alpha2(XI) chain of type XI collagen. Studies suggest that the altered protein causes hearing loss by changing the structure of type XI collagen and impairing its ability to interact with other proteins.

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Otospondylomegaepiphyseal dysplasia

At least 14 mutations in the COL11A2 gene have been found to cause otospondylomegaepiphyseal dysplasia (OSMED), a disorder characterized by skeletal abnormalities, distinctive facial features, and severe hearing loss. These signs and symptoms are similar to those of Weissenbacher-Zweymüller syndrome (described below) and to a form of Stickler syndrome classified as type III. In some cases, it can be difficult to tell these conditions apart. Some researchers believe they represent a single disorder with a range of signs and symptoms.

Most of the reported COL11A2 gene mutations that cause OSMED lead to the production of an abnormally short version of the pro-alpha2(XI) chain that is probably not incorporated into type XI collagen molecules. The defective collagen impairs the normal development of several tissues, including bones and the inner ear.

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Stickler syndrome

MedlinePlus Genetics provides information about Stickler syndrome

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Weissenbacher-Zweymüller syndrome

At least one mutation in the COL11A2 gene has been associated with Weissenbacher-Zweymüller syndrome, a disorder of bone growth characterized by skeletal abnormalities, hearing loss, and distinctive facial features. These signs and symptoms are similar to those of OSMED (described above) and to a form of Stickler syndrome classified as type III.

Like the other mutations that cause OSMED, this mutation leads to defective type XI collagen. The abnormal collagen impairs the normal development of several tissues, including bones and the inner ear.

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Other Names for This Gene

  • collagen type XI alpha 2
  • collagen, type XI, alpha 2
  • HKE5
  • PARP
  • STL3

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

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  • Chen W, Kahrizi K, Meyer NC, Riazalhosseini Y, Van Camp G, Najmabadi H, Smith RJ. Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus. J Med Genet. 2005 Oct;42(10):e61. Epub 2005 Jul 20. Citation on PubMed or Free article on PubMed Central
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  • Jakkula E, Melkoniemi M, Kiviranta I, Lohiniva J, Räinä SS, Perälä M, Warman ML, Ahonen K, Kröger H, Göring HH, Ala-Kokko L. The role of sequence variations within the genes encoding collagen II, IX and XI in non-syndromic, early-onset osteoarthritis. Osteoarthritis Cartilage. 2005 Jun;13(6):497-507. Citation on PubMed
  • McGuirt WT, Prasad SD, Griffith AJ, Kunst HP, Green GE, Shpargel KB, Runge C, Huybrechts C, Mueller RF, Lynch E, King MC, Brunner HG, Cremers CW, Takanosu M, Li SW, Arita M, Mayne R, Prockop DJ, Van Camp G, Smith RJ. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat Genet. 1999 Dec;23(4):413-9. Citation on PubMed
  • Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kääriäinen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet. 2000 Feb;66(2):368-77. Citation on PubMed or Free article on PubMed Central
  • Pihlajamaa T, Prockop DJ, Faber J, Winterpacht A, Zabel B, Giedion A, Wiesbauer P, Spranger J, Ala-Kokko L. 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). Am J Med Genet. 1998 Nov 2;80(2):115-20. Citation on PubMed
  • Ryder JJ, Garrison K, Song F, Hooper L, Skinner J, Loke Y, Loughlin J, Higgins JP, MacGregor AJ. Genetic associations in peripheral joint osteoarthritis and spinal degenerative disease: a systematic review. Ann Rheum Dis. 2008 May;67(5):584-91. Epub 2007 Aug 24. Review. Citation on PubMed
  • Tompson SW, Faqeih EA, Ala-Kokko L, Hecht JT, Miki R, Funari T, Funari VA, Nevarez L, Krakow D, Cohn DH. Dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2. Am J Med Genet A. 2012 Feb;158A(2):309-14. doi: 10.1002/ajmg.a.34406. Epub 2012 Jan 13. Citation on PubMed or Free article on PubMed Central
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