COL7A1

The COL7A1 gene provides instructions for making proteins that are used to assemble type VII collagen. Collagens are a family of proteins that strengthen and support connective tissues, such as skin, bone, tendons, and ligaments, throughout the body. In particular, type VII collagen plays an essential role in strengthening and stabilizing the skin.

The proteins produced from the COL7A1 gene, called pro-α1(VII) chains, are the components of type VII collagen. Three pro-α1(VII) chains twist together to form a triple-stranded, ropelike molecule known as a procollagen. Procollagen molecules are secreted by the cell and processed by enzymes to remove extra protein segments from the ends. Once these molecules are processed, they arrange themselves into long, thin bundles of mature type VII collagen.

Type VII collagen is the major component of structures in the skin called anchoring fibrils. These fibrils are found in a region known as the epidermal basement membrane zone, which is a two-layer membrane located between the top layer of skin, called the epidermis, and an underlying layer called the dermis. Anchoring fibrils hold the two layers of skin together by connecting the epidermal basement membrane to the dermis.

dystrophic epidermolysis bullosa - caused by mutations in the COL7A1 gene

More than 400 mutations in the COL7A1 gene have been identified in people with dystrophic epidermolysis bullosa. These mutations alter the structure or disrupt the production of type VII collagen, which impairs the ability of anchoring fibrils to connect the epidermis to the dermis. When type VII collagen is abnormal or missing, anchoring fibrils cannot form properly. As a result, friction or other minor trauma can cause the two skin layers to separate. This separation leads to the formation of blisters, which can result in extensive scarring as they heal.

The autosomal recessive types of dystrophic epidermolysis bullosa (RDEB) result from mutations in both copies of the COL7A1 gene in each cell. The most severe, classic form of this disorder is known as the Hallopeau-Siemens type (RDEB-HS). Most of the COL7A1 mutations responsible for RDEB-HS significantly reduce or eliminate the production of type VII collagen. As a result, few or no anchoring fibrils are present to connect the epidermis with the dermis. This lack of anchoring fibrils causes the severe signs and symptoms of RDEB-HS. A somewhat less severe form of autosomal recessive dystrophic epidermolysis bullosa, known as the non-Hallopeau-Siemens type (Non-HS RDEB), is caused by other types of mutations. These genetic changes allow a small amount of normal or partially functional type VII collagen to be produced.

A milder, autosomal dominant form of dystrophic epidermolysis bullosa (DDEB) results from mutations in one copy of the COL7A1 gene in each cell. In many cases, these mutations occur in a part of type VII collagen known as the collagenous region. This region gives type VII collagen its usual triple-stranded structure. It is made up of a pattern of protein building blocks (amino acids) in which every third amino acid is a glycine. Mutations that substitute other amino acids for glycine in this region can disrupt the triple-stranded structure of type VII collagen. When the abnormally shaped collagen molecules are incorporated into anchoring fibrils, they interfere with the fibrils' normal function and prevent them from effectively connecting the epidermis and the dermis. DDEB can also be caused by other types of mutations, particularly changes that affect the folding of type VII collagen.

It is unclear how COL7A1 mutations are associated with an increased risk of certain cancers, particularly squamous cell carcinoma, in people with severe types of dystrophic epidermolysis bullosa. Some research has suggested that abnormal forms of type VII collagen that retain a fragment called the NC1 domain may increase the risk of tumor formation. Other studies, however, have not found this association.