LEKTI

Lympho-Epithelial Kazal-Type-Related Inhibitor (LEKTI) is a serine protease inhibitor involved in the regulation of skin barrier formation and immune response. It is encoded by the SPINK5 (Serine Peptidase Inhibitor, Kazal Type 5) gene in humans. LEKTI is crucial for the maintenance of skin integrity and plays a significant role in preventing the entry of pathogens and allergens. Its deficiency or dysfunction is associated with several dermatological disorders, including Netherton syndrome, a severe, autosomal recessive congenital ichthyosis.

Structure and Function

LEKTI is a multidomain serine protease inhibitor that is predominantly expressed in stratified epithelia, such as the skin and mucosal surfaces. It consists of 15 domains, including one signal peptide and 14 Kazal-type serine protease inhibitor domains. This structure allows LEKTI to inhibit a broad range of serine proteases, which are enzymes involved in the degradation of proteins. By inhibiting these proteases, LEKTI plays a critical role in controlling the desquamation process, where the outer layer of the skin is shed, and in maintaining the skin's barrier function.

Genetics

The SPINK5 gene, located on chromosome 5q32, encodes the LEKTI protein. Mutations in this gene can lead to a decrease in LEKTI activity, which disrupts skin barrier function and immune response, contributing to the development of skin diseases. The most well-known condition associated with mutations in the SPINK5 gene is Netherton syndrome.

Clinical Significance

1. 1. 1. Netherton Syndrome

Netherton syndrome is a rare genetic disorder characterized by ichthyosis (scaly skin), a predisposition to atopic manifestations such as allergies, asthma, and hay fever, and immune system abnormalities. Patients with Netherton syndrome have mutations in the SPINK5 gene that lead to a functional deficiency of LEKTI. This deficiency disrupts the skin's barrier function, making it more permeable to allergens and pathogens and leading to the clinical manifestations of the syndrome.

1. 1. 1. Other Dermatological Disorders

Research suggests that variations in the expression of LEKTI may also be involved in other skin conditions, such as atopic dermatitis and psoriasis, although the exact mechanisms and the role of LEKTI in these conditions are still under investigation.

Treatment and Management

There is currently no cure for Netherton syndrome, and treatment focuses on managing symptoms and preventing complications. This may include the use of moisturizers to maintain skin hydration, topical corticosteroids to reduce inflammation, and antibiotics or antifungals to treat secondary infections. In cases where LEKTI deficiency contributes to other skin conditions, treatment aims to restore the skin's barrier function and manage symptoms.

Research Directions

Ongoing research is focused on better understanding the role of LEKTI in skin biology and its involvement in dermatological disorders. This includes exploring the potential for gene therapy to correct SPINK5 mutations and restore LEKTI function, as well as developing targeted therapies that can modulate the activity of serine proteases inhibited by LEKTI.