COL2A1

The COL2A1 gene provides instructions for making one component of type II collagen, called the pro-alpha1(II) chain. Type II collagen adds structure and strength to the connective tissues that support the body's muscles, joints, organs, and skin. Type II collagen is found primarily 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 II collagen is also part of the clear gel that fills the eyeball (the vitreous), the inner ear, and the center portion of the discs between the vertebrae in the spine (nucleus pulposus).

To construct type II collagen, three pro-alpha1(II) chains twist together to form a triple-stranded, ropelike procollagen molecule. Procollagen molecules are then processed by enzymes in the cell. Once processed, the molecules leave the cell and arrange themselves into long, thin fibrils that link to one another (cross-link) in the spaces around cells. The cross-linkages result in the formation of very strong, mature type II collagen fibers.

achondrogenesis - caused by mutations in the COL2A1 gene

Mutations in the COL2A1 gene cause a form of achondrogenesis known as type 2. Some mutations delete part of the COL2A1 gene or lead to pro-alpha1(II) chains that are missing critical segments. Other mutations change one of the protein building blocks (amino acids) used to make the pro-alpha1(II) chain. Specifically, the amino acid glycine is replaced with a different amino acid at various places in this collagen chain. All of these mutations prevent the normal production of mature type II collagen, which results in the severe skeletal abnormalities seen in this disorder.

Czech dysplasia - caused by mutations in the COL2A1 gene

All persons identified with Czech dysplasia have been found to have the same COL2A1 mutation, which was inherited from an affected parent. This mutation replaces the amino acid arginine with the amino acid cysteine (written as Arg275Cys or R275C) in the pro-alpha1(II) chain. It is not known what effect this mutation has on the pro-alpha1(II) chain. Researchers speculate that the mutation might interfere with the collagen chain's ability to form a procollagen molecule. Procollagen molecules are needed to produce mature type II collagen. A disruption in the production of type II collagen can impair bone and cartilage development, causing the signs and symptoms of Czech dysplasia.

hypochondrogenesis - caused by mutations in the COL2A1 gene

At least 18 mutations in the COL2A1 gene have been found to cause hypochondrogenesis. Some mutations delete part of the COL2A1 gene or lead to pro-alpha1(II) chains that are missing critical segments. Other mutations change one of the amino acids used to make the pro-alpha1(II) chain. Specifically, the amino acid glycine is replaced with a different amino acid at various places in this collagen chain. All of these mutations interfere with the formation of mature triple-stranded type II collagen molecules, which result in the features of hypochondrogenesis by affecting tissues that are rich in type II collagen.

Kniest dysplasia - caused by mutations in the COL2A1 gene

Most of the mutations responsible for Kniest dysplasia delete one or more DNA building blocks (nucleotides) in the COL2A1 gene. These mutations cause abnormally short pro-alpha1(II) collagen chains to be produced in the cell, which then join with longer, normal-length collagen chains. The mismatch of normal and abnormally short pro-alpha1(II) collagen chains results in abnormal type II collagen molecules that are shorter than usual. This abnormal type II collagen prevents bones and other connective tissues from developing properly, which causes short stature, joint problems, and other signs and symptoms of Kniest dysplasia.

platyspondylic lethal skeletal dysplasia, Torrance type - caused by mutations in the COL2A1 gene

Fewer than 10 mutations in the COL2A1 gene have been identified in people with platyspondylic lethal skeletal dysplasia, Torrance type. All of these mutations occur in a region of the pro-alpha1(II) chain called the C-propeptide domain, most often changing a single amino acid. These COL2A1 mutations lead to the production of an abnormal version of the pro-alpha1(II) chain that cannot be incorporated into type II collagen fibers. As a result, a reduced amount of type II collagen is produced. Instead of forming collagen molecules, the abnormal pro-alpha1(II) chains build up in cartilage cells (chondrocytes). These changes disrupt normal bone development, resulting in skeletal abnormalities, such as short arms and legs, a small chest, flattened vertebrae, and short fingers and toes, that are characteristic of platyspondylic lethal skeletal dysplasia, Torrance type.

spondyloepimetaphyseal dysplasia, Strudwick type - caused by mutations in the COL2A1 gene

All identified COL2A1 mutations that cause spondyloepimetaphyseal dysplasia, Strudwick type change one of the amino acids used to make the pro-alpha1(II) chain of type II collagen. Specifically, the amino acid glycine is replaced with a different amino acid at various places in this collagen chain. The substitution of another amino acid for glycine in this chain inhibits the formation of stable, triple-stranded, ropelike collagen molecules. This alteration in type II collagen prevents bones and other connective tissues from developing properly, which causes the short stature, skeletal abnormalities, and vision problems characteristic of spondyloepimetaphyseal dysplasia, Strudwick type.

spondyloepiphyseal dysplasia congenita - caused by mutations in the COL2A1 gene

More than 20 mutations in the COL2A1 gene have been found to cause spondyloepimetaphyseal dysplasia congenita. These mutations may result in an incorrect amino acid in the pro-alpha1(II) chain. Specifically, the amino acid glycine is replaced with a different amino acid at various places in this collagen chain. Mutations may also result in the production of an abnormally short pro-alpha1(II) chain. All of these changes interfere with the formation of mature triple-stranded type II collagen molecules. This interference results in spondyloepimetaphyseal dysplasia congenita by affecting tissues that are rich in type II collagen. Skeletal abnormalities, vision problems, and hearing loss are the most common problems seen in this disorder.

spondyloperipheral dysplasia - caused by mutations in the COL2A1 gene

At least three mutations in the COL2A1 gene have been found to cause spondyloperipheral dysplasia. All of these mutations occur in a region of the pro-alpha1(II) chain called the C-propeptide domain. The C-propeptide domain is necessary for the pro-alpha1(II) chains to attach (bind) to one another to form type II collagen. These mutations lead to the production of an abnormally short pro-alpha1(II) chain that cannot be incorporated into type II collagen fibers. As a result, cells make a reduced amount of type II collagen. Instead of forming collagen molecules, the abnormal pro-alpha1(II) chains build up in cartilage cells (chondrocytes). These changes disrupt normal bone development, resulting in flattened vertebrae, short fingers and toes, and the other features of spondyloperipheral dysplasia.

Stickler syndrome - caused by mutations in the COL2A1 gene

Several of the mutations in the COL2A1 gene that cause Stickler syndrome result in the production of an abnormally short pro-alpha1(II) chain that cannot be incorporated into a type II collagen fiber. Other mutations create a premature stop signal in the instructions for making the pro-alpha1(II) chain. As a result of these COL2A1 gene mutations, cells produce only half the normal amount of this collagen chain. This shortage causes an underproduction of type II collagen in cartilage and other tissues. A lack of type II collagen can cause overly flexible joints, distinctive facial features, hearing loss, severe nearsightedness with associated eye problems, and other signs and symptoms of Stickler syndrome.

other disorders - associated with the COL2A1 gene

Mutations in the COL2A1 gene can sometimes result in a condition known as avascular necrosis of the femoral head. This condition causes the upper ends of the thigh bones (femurs) to break down due to an inadequate blood supply and deficient bone repair. One mutation known to be responsible for the inherited form of this disorder alters the sequence of amino acids in the pro-alpha1(II) chain of type II collagen. It is unknown exactly how irregular type II collagen affects the hip joints and results in this disorder. Avascular necrosis of the femoral head usually appears in adulthood. It can lead to pain and limping and cause the legs to be of unequal length.

In some people, variations in the COL2A1 gene may increase the risk of developing osteoarthritis, a degenerative disease of joint cartilage. The variations in this gene result in amino acid changes in the pro-alpha1(II) chain of type II collagen. These changes to the collagen fibers in joints are thought to play a role in the erosion of joint cartilage, resulting in the signs and symptoms of osteoarthritis.

A large family in Japan has been identified with several different skeletal disorders resulting from a mutation in the COL2A1 gene. This mutation is responsible for avascular necrosis of the femoral head, osteoarthritis, and Legg-Calvé-Perthes disease in different family members. As in avascular necrosis of the femoral head, Legg-Calvé-Perthes disease causes breakdown of the upper ends of the thigh bones at the hip joint but onset is earlier, beginning in childhood. The cause of Legg-Calvé-Perthes disease is usually unknown. This Japanese family is the only known case in which a COL2A1 gene mutation is the cause of Legg-Calvé-Perthes disease. Researchers are looking for addition genetic and environmental factors that may underlie this condition.

Mutations in the COL2A1 gene can also result in a condition called autosomal dominant rhegmatogenous retinal detachment. Rhegmatogenous retinal detachment occurs when the retina (the part of the eye that detects light and color) tears and becomes detached from the back of the eye, leading to vision difficulties and sometimes blindness. Mutations that result in abnormal type II collagen affect the development and function of the eye.