KRT5

The KRT5 gene provides instructions for making a protein called keratin 5. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, and nails. Keratin 5 is produced in cells called keratinocytes found in the outer layer of the skin (the epidermis).

Keratin 5 partners with a similar protein, keratin 14, to form molecules called keratin intermediate filaments. These filaments assemble into strong networks that help attach keratinocytes together and anchor the epidermis to underlying layers of skin. The network of keratin intermediate filaments provides strength and resilience to the skin and protects it from being damaged by friction and other everyday physical stresses.

Researchers believe that keratin 5 may also play a role in transporting melanosomes, which are cellular structures that produce a pigment called melanin. The transport of these structures into keratinocytes is important for normal skin coloration (pigmentation).

Dowling-Degos disease - caused by mutations in the KRT5 gene

At least four mutations in the KRT5 gene have been found to cause Dowling-Degos disease. This condition is characterized by various skin abnormalities, particularly a lacy pattern of abnormally dark skin coloring (hyperpigmentation) that occurs most often in the body's folds and creases. Most of these mutations lead to the production of a keratin 5 protein that is abnormally small and nonfunctional or prevent any protein from being produced from the gene. A decrease in keratin 5 can impair the formation of keratin intermediate filaments. As a result, the normal organization of the epidermis is altered, leading to the development of different types of skin lesions. Additionally, a decrease in keratin 5 may disrupt the movement of pigment-carrying melanosomes into keratinocytes, where they are needed for normal skin pigmentation. This disruption of melanosome transport is thought to cause the pigmentation abnormalities seen in individuals with Dowling-Degos disease.

epidermolysis bullosa simplex - caused by mutations in the KRT5 gene

More than 100 mutations in the KRT5 gene have been identified in people with epidermolysis bullosa simplex, a condition that causes the skin to be very fragile and to blister easily. Most KRT5 gene changes that cause this condition alter single protein building blocks (amino acids) used to make keratin 5. The most severe form of epidermolysis bullosa simplex, the Dowling-Meara type, usually results from changes in regions of keratin 5 that are essential for the normal assembly of keratin intermediate filaments. Milder forms of the disorder, including the Weber-Cockayne and Koebner types, are often caused by changes in less critical regions of the protein. Epidermis bullosa simplex with mottled pigmentation typically results from a particular KRT5 mutation. This mutation replaces the amino acid proline with the amino acid leucine at protein position 25 (written as Pro25Leu or P25L).

The KRT5 gene mutations responsible for epidermolysis bullosa simplex change the structure and function of keratin 5, preventing it from working effectively with keratin 14 and interfering with the assembly of the keratin intermediate filament network. A disruption in this network makes keratinocytes fragile and prone to rupture. Minor trauma to the skin, such as rubbing or scratching, can cause these cells to break down, resulting in the formation of painful, fluid-filled blisters.