SPINK5: both rare and common skin disease

Abstract

Atopic dermatitis (AD or eczema) is an inflammatory skin disease with clinical manifestations presenting in early childhood, often with subsequent development of asthma. AD and asthma are examples of atopic diseases (caused by allergy) which are characterized by increased levels of IgE. During recent years, there has been a steady increase of atopic diseases in western society with prevalence of AD now at approximately 15%. Genetic mechanisms underlying complex gene traits are difficult to elucidate and the atopies are no exception. A complex interaction between various genes and environmental factors are thought to underlie AD and other atopic disease. Genetic linkage and association studies have been undertaken to try map disease loci for AD and, although no single gene has been identified unequivocally, linkage to a number of chromosomal regions has been demonstrated. For example, a major susceptibility locus on chromosome 3q21 has been identified spanning approximately 10 cM and including the genes encoding CD80 and CD86, two type-1 membrane proteins of the immunoglobulin superfamily.Clues as to a key genetic component of AD came as a result of the study of a rare recessive skin disease, Netherton's syndrome, in which atopy is characteristic. Netherton's syndrome was recently shown to be caused by mutations in the SPINK5 gene, which encodes LEKTI, a 15-domain serine protease inhibitor expressed in epithelial and mucosal surfaces and also in the thymus. Intriguingly, SPINK5 is contained within the distal end of the cytokine cluster on 5q31–33, a chromosomal region previously to have shown linkage to AD. Walley et al. [1xGene polymorphism in Netherton and common atopic disease. Walley et al. Nat. Genet. 2001; 29: 175–178Crossref | PubMed | Scopus (277)See all References[1] have recently reported an association (computed by transmission disequilibrium tests) between AD and a Glu420→Lys polymorphism in SPINK5. In addition, five more coding polymorphisms were found in this gene. Interestingly, a parent-of-origin effect was seen, with maternal Asn368 and Lys420 conveying a significantly increased risk of atopy to offspring when compared with paternally inherited alleles. A similar effect was seen with associations between AD and serum IgE concentration. One mechanistic hypothesis proposed is that the Glu420→Lys polymorphism in SPINK5 introduces an additional basic residue (optimal site for proteolysis) into the linker sequence between LEKTI proteinase inhibitor domains, which might lead to variable inhibition of various serine proteinase allergens.The role of SPINK5 in rare and common skin disease demonstrates the value of studying rare but less genetically complex diseases to gain insight into the mechanisms underlying the more common complex traits. From the identification of the genes involved in monogenic disorders and the cellular pathways involved in their clinical manifestation, parallels can be drawn to similar but more prevalent complex genetic diseases such as AD and atopy. The application of similar genetic approaches to that described by Walley and co-workers is likely to pave the way for new therapies and further understanding of AD, atopy and other multigenic disorders.