COL1A2

The COL1A2 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 COL1A2 gene produces a component of type I collagen called the pro-α2(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 COL1A2 gene

Several mutations in the COL1A2 gene have been found in people with the arthrochalasia type of Ehlers-Danlos syndrome. These mutations, which affect one copy of the COL1A2 gene in each cell, delete a segment of the pro-α2(I) chain that attaches one collagen molecule to another. The absence of this important segment prevents the normal assembly of type I collagen fibrils and alters the cross-linking between collagen molecules. These changes mainly affect tissues that are rich in type I collagen, such as the skin, bones, and tendons.

Rarely, mutations in both copies of the COL1A2 gene in each cell have been reported in people with the characteristic features of Ehlers-Danlos syndrome. These mutations prevent cells from producing any normal pro-α2(I) chains. As a result, type I collagen fibrils in the skin and other tissues cannot be assembled correctly. The presence of abnormal collagen is associated with a variety of signs and symptoms, including loose joints, cardiac problems, and other complications associated with Ehlers-Danlos syndrome.

osteogenesis imperfecta - caused by mutations in the COL1A2 gene

About 300 disease-causing COL1A2 mutations have been identified. Mutations in this gene occasionally cause osteogenesis imperfecta type I, the mildest form of this disorder. Most COL1A2 mutations, however, cause more severe forms of osteogenesis imperfecta, including types II, III, and IV.

Some COL1A2 mutations delete pieces of the gene, which leads to a pro-α2(I) chain that is missing critical regions. Other genetic changes alter the sequence of protein building blocks (amino acids) in the pro-α2(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 COL1A2 mutations prevent the normal production of type I collagen. When 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 - caused by mutations in the COL1A2 gene

Some people with COL1A2 mutations exhibit the signs and symptoms of both osteogenesis imperfecta and Ehlers-Danlos syndrome. These mutations include duplications of a large part of the gene, deletions of an important segment of the pro-α2(I) chain, and genetic changes that result in an abnormally shortened version of the pro-α2(I) chain. Mutations in the COL1A2 gene alter the structure of collagen fibrils or prevent normal cross-linking between collagen molecules. These defects weaken connective tissue, leading to the characteristic features of these two conditions.