COL1A1

The COL1A1 gene provides instructions for making part of a large molecule called type I collagen. Collagens are a family of proteins that strengthen and support many tissues in the body, including cartilage, bone, tendon, skin, and the white part of the eye (the sclera). Type I collagen is the most abundant form of collagen in the human body.

The COL1A1 gene produces a component of type I collagen called the pro-α1(I) chain. Collagens begin as procollagen molecules, which must be processed by enzymes outside the cell to remove extra protein segments from their ends. Each rope-like procollagen molecule is made up of three chains: two pro-α1(I) chains, which are produced from the COL1A1 gene, and one pro-α2(I) chain, which is produced from the COL1A2 gene.

After procollagens are processed, the resulting mature collagen molecules arrange themselves into long, thin fibrils. Individual collagen molecules are cross-linked to one another within these fibrils. The formation of cross-links results in very strong type I collagen fibrils, which are found in the spaces around cells.

Ehlers-Danlos syndrome - caused by mutations in the COL1A1 gene

Several specific mutations in the COL1A1 gene are responsible for the arthrochalasia type of Ehlers-Danlos syndrome. These genetic changes lead to the production of a pro-α1(I) chain that is missing a critical segment. The absence of this segment interferes with the assembly and structure of type I collagen molecules and the processing of these molecules into collagen fibrils. Tissues that are rich in type I collagen, such as the skin, bones, and tendons, are most affected by this change.

A mutation in the COL1A1 gene has also been shown to cause the classic type of Ehlers-Danlos syndrome. This mutation changes one of the protein building blocks (amino acids) used to build the pro-α1(I) chain. Specifically, this genetic change replaces the amino acid arginine with the amino acid cysteine at position 134 (written as Arg134Cys or R134C). The altered protein interferes with other collagen-building proteins, disrupting the structure of type I collagen fibrils and trapping collagen in the cell. Researchers believe that this COL1A1 mutation only rarely underlies the signs and symptoms of classic Ehlers-Danlos syndrome.

osteogenesis imperfecta - caused by mutations in the COL1A1 gene

Osteogenesis imperfecta is the most common disorder caused by mutations in the COL1A1 gene. More than 400 disease-causing COL1A1 mutations have been identified. Most of the mutations that are responsible for osteogenesis imperfecta type I, the mildest form of this disorder, reduce the production of pro-α1(I) chains. With fewer pro-α1(I) chains available, cells can make only half the normal amount of type I collagen. A shortage of this critical protein underlies the bone fragility and other characteristic features of osteogenesis imperfecta type I.

Several types of mutations in the COL1A1 gene cause the more severe forms of osteogenesis imperfecta, including types II, III, and IV. Some of these mutations delete segments of DNA from the COL1A1 gene, resulting in an abnormally shortened, often nonfunctional pro-α1(I) chain. Other genetic changes alter the sequence of amino acids in the pro-α1(I) chain, usually replacing the amino acid glycine with a different amino acid. In some cases, amino acid substitutions alter one end of the protein chain (called the C-terminus), which interferes with the assembly of collagen molecules. These COL1A1 mutations lead to the production of abnormal versions of type I collagen. When this abnormal collagen is incorporated into developing bones and other connective tissues, it causes the serious medical problems associated with severe forms of osteogenesis imperfecta.

other disorders - associated with the COL1A1 gene

Some people with COL1A1 mutations exhibit the signs and symptoms of both osteogenesis imperfecta and Ehlers-Danlos syndrome. These mutations replace the amino acid glycine with a different amino acid in the pro-α1(I) chain, which impairs the interactions between protein chains. The resulting abnormal type I collagen fibrils weaken connective tissue, causing the signs and symptoms associated with these two conditions.

A mutation in the COL1A1 gene is also responsible for some cases of infantile cortical hyperostosis, commonly known as Caffey disease. The signs and symptoms of Caffey disease are usually apparent by the time an infant is 5 months old. This condition is characterized by irritability, inflammation of soft tissues (muscles, for example), and excessive new bone formation. The bone abnormalities mainly affect the jawbone, collarbones (clavicles), and the shafts (diaphyses) of long bones in the arms and legs. For unknown reasons, these changes occur mostly in the first year of life and lessen over time. Through a normal process called bone remodeling, which replaces old bone tissue with new bone, the excess bone is usually gone by the age of 2. The mutation responsible for this condition replaces the amino acid arginine with the amino acid cysteine at protein position 836 (written as Arg836Cys or R836C). This mutation results in the production of type I collagen fibrils that are variable in size and shape, which most likely leads to the signs and symptoms of this disorder.

A common variation in the COL1A1 gene (called a polymorphism) appears to increase the risk of developing osteoporosis. Osteoporosis is a condition that makes bones progressively more brittle and prone to fracture. This polymorphism, which occurs in a regulatory region of the COL1A1 gene, likely affects the production of type I collagen. Several studies have shown that women with this genetic change are more likely to have signs of osteoporosis, particularly low bone density and bone fractures, than are women without the change. This variation is only one of many factors that can increase the risk of osteoporosis.