SPINK5

At least 70 SPINK5 gene mutations have been identified in people with Netherton syndrome, a disorder involving skin and hair abnormalities and a high risk of allergies, asthma, and an inflammatory skin condition called eczema. Mutations in the SPINK5 gene result in a LEKT1 protein that is unable to control serine peptidase activity. The lack of LEKT1 function allows the serine peptidases to be abnormally active and break down too many proteins in the stratum corneum. As a result, excessive skin shedding takes place, and the stratum corneum is unusually thin and breaks down easily, resulting in the skin abnormalities that occur in Netherton syndrome. Loss of LEKT1 function also results in abnormal hair growth. The immune dysfunction that leads to allergies, asthma, and eczema in people with Netherton syndrome likely arises from a lack of LEKT1 control of peptidases involved in the triggering of immune system function. Excessive activation of the immune system caused by invasion of microbes in the abnormal skin is also thought to be involved.

Normal variations (polymorphisms) in the SPINK5 gene have been associated with an increased risk of abnormal triggering (hypersensitivity) of the immune system, known as atopy. Atopy leads to disorders such as allergies, eczema, and asthma. SPINK5 gene variations may affect the ability of LEKT1 to control peptidases involved in triggering the immune system, leading to an increased risk of these disorders.