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Definition of COL2A1

COL2A1: The gene responsible for the production of the alpha1(II) chain of type II collagen. Mutations in the COL2A1 gene lead to a number of different heritable skeletal disorders, including achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, spondyloepimetaphyseal dysplasia of the Strudwick type, spondyloepiphyseal dysplasia congenita, and Stickler syndrome.

Type II collagen, which adds structure and strength to connective tissues, is found primarily in cartilage, the gel that fills the eyeball (vitreous body), inner ear, and the center portion of the discs between the vertebrae in the spine (nucleus pulposus).

There are two forms of type II collagen made in the body. One version, type IIA, is made mainly in the vitreous body of the eye. The second version, type IIB, is preferentially produced in adult cartilage tissue.

Collagen II is initially produced as type II procollagen, a protein consisting of three pro-alpha1(II) chains twisted together to form a triple-stranded helical (spiral-shaped) molecule. While in the cell, enzymes modify certain amino acids (the building blocks of proteins), specifically lysine and proline, by adding chemical groups that are necessary for the strands to come together in a stable structure and then cross-link with other molecules. Other enzymes add sugars to the protein. The triple-stranded type II procollagen molecule leaves the cell and is converted to collagen by enzymes that clip small segments off both ends. The collagen molecules arrange themselves into long, thin fibrils outside of the cell. The fibrils come together in side-by-side groups to form collagen fibers. Cross-linking between molecules in fibrils produces a very stable protein structure, which contributes to collagen's tissue-strengthening function.

Achondrogenesis, type II -- Mutations in the COL2A1 gene are responsible for achondrogenesis, type II. Many of the mutations in this gene cause an amino acid substitution; specifically, the amino acid glycine is replaced by another amino acid in the part of the protein that is responsible for stable triple-helix formation. These mutations sometimes cause the pro-alpha1(II) type II collagen chains to be retained in the cell leading to little or no production of type II collagen. Other mutations lead to missing segments in the pro-alpha1(II) type II collagen chains, resulting in the production of chains unsuitable for proper collagen production. In a few cases, pieces of the COL2A1 gene are missing. This type of mutation makes incomplete proteins that may not be processed correctly or may not even assemble into collagen fibers. All of these changes interfere with the formation of mature triple-stranded type II collagen molecules. Type II collagen is found primarily in cartilage, which is a precursor of bone, and is critical for embryonic development and growth. Because of this critical role, mutations in the COL2A1 gene can cause very severe skeletal abnormalities that are usually lethal before birth or in early infancy.

Hypochondrogenesis -- Mutations in the COL2A1 gene are responsible for hypochondrogenesis. Many of the mutations in this gene cause an amino acid substitution; specifically, the amino acid glycine is replaced by another amino acid. This change sometimes leads to retention of the pro-alpha1(II) type II collagen chain inside the cell. It can also inhibit the formation of a stable, triple-stranded, helical collagen molecule in chains that are secreted. Other mutations lead to missing segments in the pro-alpha1(II) type II collagen chains, resulting in the production of chains unsuitable for proper collagen production. In a few cases, pieces of the COL2A1 gene are missing. This type of mutation makes incomplete proteins that may not be processed correctly or may not even assemble into collagen fibers. All of these changes interfere with the formation of mature triple-stranded type II collagen molecules. Type II collagen is found primarily in cartilage and is critical for embryonic development and growth. Because of this critical role, mutations in the COL2A1 gene can result in very severe skeletal abnormalities that are usually lethal before birth or in early infancy.

Kniest dysplasia -- Kniest dysplasia is caused by mutations in the COL2A1 gene. The mutations cause shorter-than-normal pro-alpha1(II) type II collagen protein chains to be produced. When these chains interact to form triple-helical molecules, these short chains are combined with longer, normal-length chains. The resulting abnormal molecule becomes shorter than normal, causing the signs and symptoms of Kniest dysplasia.

Spondyloepimetaphyseal dysplasia, Strudwick type -- Mutations in the COL2A1 gene can cause spondyloepimetaphyseal dysplasia, Strudwick type. All of the mutations characterized to date in COL2A1 cause an amino acid substitution; specifically, the amino acid glycine is replaced by another amino acid. This change inhibits the formation of stable, triple-stranded, helical collagen molecules. This type of collagen is found primarily in cartilage, the vitreous body of the eye, the inner ear, and the center portion of vertebral discs. Type II collagen is also critical for embryonic development and growth. Because of this critical role, mutations in the COL2A1 gene can result in skeletal and eye aberrations.

Spondyloepiphyseal dysplasia congenita -- Mutations in the COL2A1 gene cause spondyloepimetaphyseal dysplasia congenita. Some mutations cause segments of the gene to be skipped when a protein is being made, resulting in shorter-than-normal pro-alpha1(II) type II collagen chains. Some of these short chains are integrated into mature type II collagen, while other chains are retained inside the cell, making them unusable for collagen production. Other mutations cause an incorrect amino acid replacement in the pro-alpha1(II) type II collagen chain. This mistake changes the function, and sometimes the structure of the collagen, and inhibits the normal production of mature type II collagen. Mutations in the COL2A1 gene can result in the skeletal and eye abnormalities seen in this syndrome.

Stickler syndrome -- Mutations in the COL2A1 gene are the cause of Stickler syndrome, COL2A1. Some of these mutations result in the production of a protein that is too short to be incorporated into a functional type II collagen molecule. Most of the COL2A1 mutations that cause Stickler syndrome however involve a premature termination signal in on copy of the gene. This results in mRNA that is broken down by the cell before a protein can be made. Because of this, cells produce only half of the normal amount of pro-alpha 1(II) type II collagen chains. This shortage results in underproduction of type II collagen in cartilage, the eye, inner ear, and the center portion of vertebral discs, causing the symptoms of Stickler syndrome, COL2A1.

The COL2A1 gene is located on the long (q) arm of chromosome 12 in region 12q13.11-13.2.

Source: MedTerms™ Medical Dictionary
http://www.medterms.com/script/main/art.asp?articlekey=34100
Last Editorial Review: 6/14/2012

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