Epidermolytic hyperkeratosis

Dozens of mutations in the KRT1 gene have been found in people with epidermolytic hyperkeratosis. This condition is a skin disorder characterized by red, blistering skin at an early age and thick skin (hyperkeratosis) later in life. People with KRT1 gene mutations typically have PS-type epidermolytic hyperkeratosis, which features thick skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis) in addition to other parts of the body.

Most KRT1 gene mutations associated with epidermolytic hyperkeratosis change a single protein building block (amino acid) in the keratin 1 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 1 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 weaker 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.

Other disorders

KRT1 gene mutations are involved in many other skin disorders. In several of these conditions, there is palmoplantar hyperkeratosis, but the skin on other parts of the body is usually not affected. A condition called epidermolytic palmoplantar keratoderma caused by KRT1 gene mutations is relatively mild. Affected individuals typically have palmoplantar hyperkeratosis with detachment or loosening of the epidermis (epidermolysis), usually seen as blistering. People with nonepidermolytic palmoplantar keratoderma have palmoplantar hyperkeratosis with no evidence of epidermolysis. In striate palmoplantar keratoderma type 3, the skin thickening on the palms and soles follows a specific pattern.

KRT1 gene mutations are also responsible for a skin disorder called Curth-Macklin ichthyosis hystrix. This condition involves severe hyperkeratosis on the palms and soles and sometimes the skin over large joints or on the torso. This condition is distinguished by specific changes in the keratinocytes.

Another skin condition caused by genetic changes in the KRT1 gene called cyclic ichthyosis with epidermolytic hyperkeratosis is similar to epidermolytic hyperkeratosis, but the skin changes disappear for short periods, then recur. The recurrent skin changes can last for weeks or months.