LAMA3

The LAMA3 gene provides instructions for making one part (subunit) of a protein called laminin 332 (formerly known as laminin 5). This protein is made up of three subunits, called alpha, beta, and gamma. The LAMA3 gene carries instructions for the alpha subunit; the beta and gamma subunits are produced from other genes.

Laminins are a group of proteins that regulate cell growth, cell movement (motility), and the attachment of cells to one another (adhesion). They are also involved in the formation and organization of basement membranes, which are thin, sheet-like structures that separate and support cells in many tissues. Laminin 332 has a particularly important role in the basement membrane that underlies the top layer of skin (the epidermis). This membrane gives strength and resiliency to the skin and creates an additional barrier between the body and its surrounding environment. Laminin 332 is a major component of fibers called anchoring filaments, which connect the two layers of the basement membrane and help hold the skin together.

Studies suggest that laminin 332 also has several other functions. This protein appears to be important for wound healing. Additionally, researchers have proposed roles for laminin 332 in the clear outer covering of the eye (the cornea) and in the development of tooth enamel.

junctional epidermolysis bullosa - caused by mutations in the LAMA3 gene

More than 30 mutations in the LAMA3 gene have been identified in people with junctional epidermolysis bullosa (JEB). The more severe form of the disease, known as Herlitz JEB, usually results from mutations that severely disrupt the production of functional laminin 332. Most of these mutations lead to a premature stop signal in the instructions for making the alpha subunit of laminin 332, which prevents the assembly of this protein. Without laminin 332, the epidermis is only weakly connected to the underlying layers of skin. Friction or other minor trauma (such as rubbing or scratching) can cause the skin layers to separate, leading to the formation of blisters. Infants with Herlitz JEB develop widespread blistering that causes life-threatening complications.

Other LAMA3 gene mutations cause the milder form of junctional epidermolysis bullosa, non-Herlitz JEB. Some of these mutations alter single protein building blocks (amino acids) in the alpha subunit of laminin 332. Others add or delete a small number of amino acids in the alpha subunit or change the way the gene's instructions are used to make the subunit. The genetic changes responsible for non-Herlitz JEB usually lead to the production of a laminin 332 protein that retains some of its function. Affected individuals experience blistering, but it may be limited to the hands, feet, knees, and elbows and often improves after the newborn period.

other disorders - caused by mutations in the LAMA3 gene

A mutation in the LAMA3 gene has been found to cause laryngo-onycho-cutaneous syndrome, also known as LOGIC or Shabbir syndrome. This rare disorder has been identified in families of Punjabi background from India and Pakistan. It is characterized by chronic skin ulcers and the widespread formation of red, bumpy patches called granulation tissue. A buildup of granulation tissue in different parts of the body can lead to serious complications, including infections, vision loss, and blockage of the airway. Other features of laryngo-onycho-cutaneous syndrome include malformed nails and irregular tooth enamel.

The mutation responsible for laryngo-onycho-cutaneous syndrome inserts an extra DNA building block (base pair) near one end of the LAMA3 gene (written as 151insG). This mutation alters the structure of the alpha subunit of laminin 332, and the resulting protein cannot effectively attach the epidermis to underlying layers of skin or regulate wound healing. These abnormalities of laminin 332 cause the chronic skin ulceration and overgrowth of granulation tissue that are characteristic of laryngo-onycho-cutaneous syndrome.