Epidermolytic hyperkeratosis

Dozens of mutations in the KRT10 gene have been found in people with epidermolytic hyperkeratosis. This condition is characterized by red, blistering skin at an early age and thick skin (hyperkeratosis) later in life. People with KRT10 gene mutations typically have NPS-type epidermolytic hyperkeratosis, which features thick skin on many parts of the body but not the palms of the hands or soles of the feet.

Most KRT10 gene mutations associated with epidermolytic hyperkeratosis change a single protein building block (amino acid) in the keratin 10 protein. These amino acid changes commonly occur in regions of the protein that play a role in intermediate filament formation. The mutations alter the keratin 10 protein and seem to affect how intermediate filaments interact with each other to form networks. The altered proteins still form intermediate filaments, but the intermediate filament networks are disorganized and do not function normally. Without a strong network, skin cells become fragile and are easily damaged, which can lead to blistering in response to friction or mild trauma. It is unclear how these mutations cause the overgrowth of keratinocytes that results in hyperkeratotic skin.

Ichthyosis with confetti

Mutations in the KRT10 gene can cause another skin disorder known as ichthyosis with confetti (also called congenital reticular ichthyosiform erythroderma), which is characterized by red, scaly skin all over the body with small patches of normal skin that look like confetti. The patches of normal skin increase in number and size with age. The KRT10 gene mutations involved in this condition, which are initially found in every cell of the body, alter the genetic sequence that is used as a blueprint for protein production, leading to production of abnormal keratin 10 protein. The abnormal protein includes a region at the end with an excess of the amino acid arginine; this arginine-rich region is not found in the normal keratin 10 protein. Researchers believe that this abnormal amino acid sequence directs the protein into the nucleus of the cell, where it cannot form the strong network of intermediate filaments. Loss of this network disrupts the outer layer of skin, contributing to the development of red, scaly skin.

In some abnormal cells, the mutated gene corrects itself through a complex process by which genetic material is exchanged between chromosomes. As a result, normal keratin 10 protein is produced and remains in the cytoplasm. The cell becomes normal and, as it continues to grow and divide, forms patches of normal skin in people with ichthyosis with confetti.

Other disorders

Cyclic ichthyosis with epidermolytic hyperkeratosis is another skin disorder caused by mutations in the KRT10 gene. This condition is similar to epidermolytic hyperkeratosis (described above), but the skin changes disappear for short periods, and then recur. The recurrent skin changes can last for weeks or months.