SPINK5 gene

SPINK is the acronym for "Serine Peptidase Inhibitor Kazal" and comprises a gene family located on different chromosomes. The members of this gene family code for the SPINK protease inhibitor family of the Kazal type (SPINK). These are serine peptidase inhibitors with broad efficacy. The SPINK protease inhibitors contain at least one inhibitory Kazal domain that binds them to their target, the serine proteases. This inhibits their proteolytic functions. This regulatory inhibitory function and its fine-tuning is of fundamental importance for many epithelia.

SPINK5 is the acronym for "Serine protease inhibitor Kazal-type 5". The human SPINK5 gene is located on chromosome 5q31-q32 and encodes the LEKTI protein, a fundamentally important serine protease inhibitor. LEKTI is expressed in epithelia, thymus, tonsils, parathyroid gland and trachea. It can also be detected in the stratum granulosum and stratum corneum of the epidermis and in the skin appendages.

The protease inhibitor LEKTI inhibits a number of serine proteases such as plasmin, trypsin, subtilisin A, cathepsin G or elastase as well as epidermal transglutaminase.

The "hyperactivity" of these proteolytic enzymes caused by a LEKTI deficiency leads to a significant disruption of the function of the epidermal barrier. This occurs via increased degradation of desmoglein 1 and increased degradation of desmosomes. Clinically, this manifests itself in a disturbed skin barrier, which facilitates the penetration of allergens into the skin. The special type of scaling(corneolytic scaling) in certain skin diseases (e.g. Netherton syndrome) is also due to the increased activity of these proteolytic enzymes.

To date, 5 missense mutations in the Spink5 gene (SNP ID:111637,1003180, 1004147, 1004347, 1005258) have been described, all of which are associated with the clinical phenotype of Netherton syndrome (MIM:256500). This is an autosomal recessive congenital ichthyosis associated with hair shaft abnormalities and immune system abnormalities.

Clinical features are:

• Ichthyosis linearis circumflexa
• an ichthyosiform erythroderma
• Trichorrhexis invaginata (bamboo hair)
• as well as signs of an atopic symptom complex (see Netherton syndrome below).

The high postnatal mortality is due to failure to thrive, infections and dehydration.

In eosinophilic esophagitis , SPINK5 (as well as SPINK7) is only expressed to a small extent. The absence of SPINK7 in the epithelial cells of the oesophagus appears to lead to a dysfunction of the epithelial barrier in humans and is associated with the clinical picture of "eosinophilic oesophagitis (EoE) (Lyles J et al. 2019).

1. ComèI M (1949) Ichthyosis linearis circumflexa. Dermatologica 978: 133-136
2. Kato A et al (2003) Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 148: 665-669
3. Lyles J et al.(2019) Role of genetics, environment, and their interactions in the pathogenesis of eosinophilic esophagitis. Curr Opin Immunol 60:46-53.
4. Mitsudo K et al. (2003) Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry 42: 3874-3881
5. Netherton EW (1958) A unique case of trichorrhexis nodosa; bamboo hairs. Arch Dermatol 78: 483-487
6. Salt M (2015) Netherton syndrome. A novel mutation leads to the full spectrum of typical features of Netherton syndrome. JDDG 13: 691-692
7. Yerebakan O et al (2002) Netherton syndrome associated with idiopathic congenital hemihypertrophy. Pediatr Dermatol 19: 345-348