KRT6A

The KRT6A gene provides instructions for making a protein called keratin 6a or K6a. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, nails, and similar tissues. Keratin 6a is produced in the nails, the skin on the palms of the hands and soles of the feet, and the oral mucosa that lines the inside of the mouth.

Keratin 6a partners with a similar protein, keratin 16, to form molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resiliency to the skin, nails, and other tissues. Networks of keratin filaments protect these tissues from being damaged by friction and other everyday physical stresses. Keratin 6a is also among several keratins involved in wound healing.

pachyonychia congenita - caused by mutations in the KRT6A gene

More than 20 mutations in the KRT6A gene have been identified in people with pachyonychia congenita type 1 (PC-1). Most of these mutations change single protein building blocks (amino acids) in keratin 6a. A few mutations add or delete a small number of amino acids.

The KRT6A mutations responsible for PC-1 change the structure of keratin 6a, preventing it from working effectively with keratin 16 and interfering with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of painful blisters and calluses. Additionally, fragile skin cells may abnormally produce more keratin in response to damage, which makes the skin problems worse.

Defective keratin 6a also disrupts the growth and function of cells in the nails and oral mucosa, which explains why the signs and symptoms of PC-1 also affect these tissues.