The inhibitory activities of the LEKTI domain 4 (D4) and D6 WT and AD-associated mutants on the enzyme activities of KLK5 and KLK7 were compared using fluorogenic substrates.
Mutations in the human filaggrin gene (FLG) are the most significant and well-replicated genetic mutation associated with AD, and other mutations associated with epidermal barriers such as SPINK5, FLG-2, SPRR3, and CLDN1 have all been linked to AD.
Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (ie, hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (ie, SPRR3); mattrin, which is encoded by TMEM79 and regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor lymphoepithelial Kazal-type trypsin inhibitor type 1; and the fatty acid transporter fatty acid transport protein 4 have all been linked to AD.
For the four non-synonymous SNPs, A1103G(Asn368Ser), G1156A(Asp386Asn), G1258A(Glu420Lys), G2475T(Glu825Asp) in SPINK5, the allelic frequencies in the AD cohort were 0.55 for 1103G, 0.57 for 1156A, 0.54for 1258A, 0.62 for 2475T, consistent with those already published in the original British and Japanese cohorts.
Several studies also reported genetic association between the multifactorial disease atopic dermatitis (AD) and a frequent and non-conservative LEKTI variant, E420K, in different populations.
Yet, recent information suggests that the inflammation in AD instead is initiated by inherited insults to the barrier, including a strong association between mutations in FILAGGRIN and SPINK5 in Netherton syndrome, the latter of which provides an important clue that AD is provoked by excess serine protease activity.
We also found that four SNPs [rs17718511 (P = 0.033), rs17860502 (P = 0.031), rs60978485 (P = 0.005), rs17718737 (P = 0.023)] and the haplotype TAA (P = 0.02) in the SPINK5 gene showed associations with the susceptibility of the allergic type of AD (ADe).
There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE.
Finally, we discuss the pathophysiological implications of LEKTI-1 in skin biology as well as its contribution to the pathogenesis of Netherton Syndrome and its potential involvement in atopic dermatitis.
The study also disclosed the necessity of functional analyses in addition to genetic investigations to gain further and more detailed insights into the role of LEKTI in AD.
Recently, single nucleotide polymorphism (SNP) of the SPINK5 was shown to be significantly associated with atopy, atopic dermatitis, asthma, and total serum IgE.
These results suggest that SPINK5Glu420Lys polymorphism may be associated with certain asthma phenotypes characterized by the concomitant expression of asthma and atopic dermatitis or SPT reactivity.
To investigate the expression of LEKTI in the skin of patients with NS in comparison with normal controls and patients with other skin conditions, namely atopic dermatitis, psoriasis and nonbullous ichthyosiform erythroderma.