InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Dermatology » "Current Genetics in Dermatology", book edited by Naoki Oiso, ISBN 978-953-51-0971-6, Published: February 6, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 5

LEKTI: Netherton Syndrome and Atopic Dermatitis

By Naoki Oiso and Akira Kawada
DOI: 10.5772/53574

Article top

LEKTI: Netherton Syndrome and Atopic Dermatitis

Naoki Oiso and Akira Kawada

1. Introduction

Netherton syndrome is an uncommon autosomal recessive disorder characterized by congenital ichthyosis with defective cornification, bamboo hair, and severe atopic manifestation. It is caused by mutations in SPINK5. Atopic dermatitis is shown to be associated with polymorphisms in SPINK5.

In 1958, Netherton described the bamboo-like deformity in the fragile hairs in a girl with erythematous scaly dermatitis.[2] In 1985, Greene and Muller emphasized the triad of Netherton syndrome: ichthyosis, atopy, and trichorrhexis invaginata.[3] In 2000, Chavanas et al. identified eleven different mutations in SPINK5 in 13 families with Netherton syndrome.[4] Their finding disclosed a critical role of the serine protease inhibitor lymphoepithelial Kazal-type related inhibitor (LEKTI) in epidermal barrier function and immunity, suggesting a sequential pathway for high serum IgE levels and atopic manifestations.[4] In 2005, Descargues et al. found that LEKTI is a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event.[5] In 2010, Sales showed that a pathogenic matriptase-pro-kallikrein pathway could operate in a variety of physiological and pathological processes.[6] Thus, the study of Netherton syndrome contributes not only elucidation of pathogenesis of the disorder itself but also understanding of structure of the epidermis and immune and inflammatory processes including atopic dermatitis.

In this session, we summarize (1) the clinical features of Netherton syndrome, (2) the genetic relationship of SPINK5 to atopic dermatitis, and (3) the molecular functions.

2. The clinical features of Netherton syndrome

Netherton syndrome is an uncommon autosomal recessive disease characterized by ichthyosis linearis circumflexa and/or congenital ichthyosiform erythroderma, hair shaft defects including trichorrhexis invaginata, trichorrhexis nodosa and pili torti and atopic manifestations with an elevated IgE level, frequent asthma and food allergies.[1] It is caused by mutations in SPINK5 encoding LEKTI.

The infants with Netherton syndrome commonly show a generalized erythroderma covered by fine, translucent scales, which can be difficult to distinguish clinically from erythrodermic psoriasis, non-bullous congenital ichthyosiform erythroderma, or other infantile erythrodermas.[7] Electron microscopy is useful for diagnosis. It illustrates premature lamellar body secretions and foci of electron-dense materials in the intercellular spaces of stratum corneum.[7] Patients with a mild phenotype of ichthyosis linearis circumflexa on the palms and soles will have mutations located downstream near the C-terminal end, while a severe erythrodermic phenotype will be associated with nucleotide changes with early truncations in SPINK5.[8, 9]

Trichorrhexis invaginata (bamboo hair) is a focal defect of the hair shaft that produces development of torsion nodules and invaginated nodules.[1] Invagination of affected hairs is caused by softness of the cortex in the keratogenous zone because of an incomplete formation of disulfide bonds.[10]

Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity.[11] This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopic dermatitis-like lesions in Netherton syndrome.[11] Uncontrolled kallikreins (KLK)s activity in Netherton syndrome epidermis can trigger atopic dermatitis-like lesions, independently of the environment and the adaptive immune system.[11]

3. The genetic relationship of SPINK5 to atopic dermatitis

Atopic dermatitis is a chronic and relapsing inflammatory skin disorder caused by multiple genetic and environmental factors. A recent genome-wide association studies for atopic dermatitis identified susceptibility loci at 1q21.3 (FLG), 5q22.1 (TMEM232 and SLC25A46) and 20q13.33 (TNFRSF6B and ZGPAT) in the Chinese samples (4,636 cases and 13,559 controls),[12] and a genome-wide association meta-analysis detected susceptibility loci at 11q13.5 (OVOL1), 19p13.2 (ACTL9), and 5q22.1 (KIF3A) in 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and an additional 5,419 affected individuals and 19,833 controls from 14 studies.[13] Andiappan et al. showed no evidence of association of the locus at 5q22.1, even though the effect sizes in the Singaporean Chinese population are similar to that reported in Sun et al.[12, 14] These results indicate that atopic dermatitis is more multi-factors-involved and complicated disorder than vitiligo and alopecia areata.[15, 16]

Association of SPINK5 gene polymorphisms with atopic dermatitis has been shown in case-control studies,[17-20] even though genome-wide association studies for atopic dermatisis have not identified the statistic significance. It would be indispensable to accumulate patients with typical atopic dramatis, which should be classified into the extrinsic or intrinsic types, and distinct healthy controls with no family and personal history of atopic dermatitis, allergic rhinitis and/or asthma for next investigation of genome-wide association studies for atopic dermatitis.

Fortugno et al. investigated the functional difference between representative associated polymorphism, Glu420Lys, because glutamic acid (Glu E) is an acidic amino acid and lysine (Lys K) is a basic.[21] They showed increased epidermal protease activity correlates with reduced desmoglein 1 protein expression and accelerated profilaggrin proteolysis under the presence of residue 420K within the SPINK5 sequence, contributing to defective skin barrier permeability.[21] They found that epidermis with homozygous lysine residues in codon 420 in SPINK5 displays an increased expression of the proallergic cytokine thymic stromal lymphopoietin (TSLP).[21] Further functional analysis would shed light on the involvement of the decreased activity of LEKTI in atopic dermatitis.

4. The molecular functions

The epidermis consists of the basal layer, the spinous layer, the granular layer and the cornified layer. The hair follicle is constructed by the inner root sheath, the outer root sheath and the hair bulb. LEKTI is expressed in the granular layer of the epidermis and in the inner root sheet of hair follicle and acts as an inhibitor of multiple serine proteases.4 LEPTI contains fifteen serine protease inhibitor domains and its proteolytic fragments inhibit epidermal proteases.22-28 LEPTI can inhibit the epidermal serine protease KLK5, KLK6, KLK7, KLK13 and KLK14.29 LEKTI-domain 6 was shown to specifically inhibit KLK5 and KLK7 in the mid-to-high nanomolar range.[30] Thus, protease inhibitors such as LEPTI are crucial players for controlling protease activity.

KLK5 can cleave desmoglein 1, inducing the detachment of stratum corneum and subsequent severe skin barrier defect which is associated with high permeability of various allergens. Unrepressed KLK5 activity can be present in loss-of-functional mutation in SPINK5 in Netherton syndrome and decreased functional polymorphisms in SPINK5 in atopic dermatitis. Unrestrained KLK5 activates an autonomous protease-activated-receptor-2 (PAR2) signaling, resulting in the production of major-pro-inflammatory molecules and pro-T helper 2 cytokines such as TSLP.[31] The specific KLK5-PAR-2-TSLP pathway induces atopic dermatitis-like lesions in Netherton syndrome and atopic dermatitis in individuals with predisposed polymorphisms.

KLK7 is involved in stratum corneum desquamation via the disruption of corneodesmosomes and the cell-cell adhesion junctions of corneocytes by hydrolyzing the two mayor cadherins (corneodesmosin and desmocollin 1) in the extracellular region of the junctions.[32]

Matriptase is a transmembrane tripsin-like serine protease having the capacity of autoactivation and subsequent occurrence of proteolytic cascade reactions.[33, 34] Sales et al. showed that matriptase is an efficient activator of epidermal pro-KLKs that co-localize with LEKTI at the granular-transitional layer boundary where epidermal separation takes place in Netherton syndrome.[6] They demonstrated that all the central manifestations of Netherton syndrome in LEKTI-deficient mice, such as aberrant proteolytic activity in the lower epidermis, corneodesmosome fragility, stratum corneum loss and skin inflammation, depend on the epidermal expression of matriptase.[6] Thus, pro-KLKs might be activated as KLKs which trigger excess proteolytic function under the functional loss of LEKTI in Netherton syndrome or functional insufficiency of LEKTI in atopic dermatitis with decreased functional polymorphisms in SPINK5.

The functional loss or insufficiency of LEKTI induces relative excess activation of serine protease toward severe skin allergy.

5. Conclusion

Recently, studies for the interaction between proteases and protease inhibitors are focused on the elucidation of pathogenesis of Netherton syndrome, atopic dermatitis, asthma, and food allergies. Atopic manifestation with an elevated IgE level in Netherton syndrome prompted researches to investigate the genetic relationship between atopic dermatitis and genetic polymorphisms. LEKTI encoded by functionally decreased polymorphisms can alter proteolytic activation and protease deregulation. The relationship between atopic dermatitis and improper cornification has been focused not only in model mice of Netherton syndrome but also in flaky tail mice with double filaggrin and loricrin deficiencies.[35] Further study will discover more precise mechanism in cornification, which would provide novel strategies for effective treatment for Netherton syndrome and atopic dermatitis.


1 - J. D Sun, K. G Linden, Netherton syndrome: successful use of topical tacrolimus and pimecrolimus in four siblings. Int J Dermatol 2006456937
2 - E. W Netherton, A unique cAMA Arch Dermse of trichorrhexis nodosa; bamboo hairs.AMA Arch Derm 1958784837
3 - S. L Greene, S. A Muller, Netherton’s syndrome. Report of a case and review of the literature. J Am Acad Dermatol 19851332937
4 - S Chavanas, C Bodemer, A Rochat, et alMutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.Nat Genet 2000251412
5 - P Descargues, C Deraison, C Bonnart, et alSpink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity.Nat Genet 2005375665
6 - K. U Sales, A Masedunskas, A. L Bey, et alMatriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndromeNat Genet 20104267683
7 - M Fartasch, M. L Williams, P. M Elias, et alAltered lamellar body secretion and stratum corneum membrane structure in Netherton syndrome: differentiation from other infantile erythrodermas and pathogenic implications.Arch Dermatol 199913582332
8 - E Sprecher, S Chavanas, DiGiovanna JJ et al. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J Invest Dermatol 200111717987
9 - Y Mizuno, Y Suga, S Muramatsu, et alA Japanese infant with localized ichthyosis linearis circumflexa on the palms and soles harbouring a compound heterozygous mutation in the SPINK5 geneBr J Dermatol 20051536613
10 - M Ito, K Ito, K Hashimoto, Pathogenesis in trichorrhexis invaginata (bamboo hair).J Invest Dermatol 19848316
11 - A Briot, C Deraison, M Lacroix, et alKallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndromeJ Exp Med 2009206113547
12 - L. D Sun, F. L Xiao, Y Li, et alGenome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.Nat Genet 2011436904
13 - L Paternoster, M Standl, C. M Chen, et alMeta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis.Nat Genet 20114418792
14 - A. K Andiappan, J. N Foo, M. W Choy, et alValidation of GWAS loci for atopic dermatitis in a Singapore Chinese population.J Invest Dermatol 201213215057
15 - Y Jin, S. A Birlea, P. R Fain, et alGenome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.Nat Genet 20124467680
16 - L Petukhova, M Duvic, M Hordinsky, et alGenome-wide association study in alopecia areata implicates both innate and adaptive immunityNature20104661137
17 - A. J Walley, S Chavanas, M. F Moffatt, et alGene polymorphism in Netherton and common atopic disease.Nat Genet 2001291758
18 - A Kato, K Fukai, N Oiso, et alAssociation of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese populationBr J Dermatol 20031486659
19 - C. C Lan, H. P Tu, C. S Wu, et alDistinct SPINK5 and IL-31 polymorphisms are associated with atopic eczema and non-atopic hand dermatitis in Taiwanese nursing population.Exp Dermatol 2011209759
20 - L. P Zhao, Z Di, L Zhang, et alAssociation of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China.J Eur Acad Dermatol Venereol 2012265727
21 - P Fortugno, L Furio, M Teson, et alThe 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis.Hum Mol Genet, in press.
22 - E Bitoun, A Micheloni, L Lamant, et alLEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 200312241730
23 - T Egelrud, M Brattsand, P Kreutzmann, et alhK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br J Dermatol 200515312003
24 - C. A Borgono, I. P Michael, N Komatsu, et alA potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 2007282364052
25 - C Deraison, C Bonnart, F Lopez, et alLEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 200718360719
26 - P Ovaere, S Lippens, P Vandenabeele, et alThe emerging roles of serine protease cascades in the epidermisTrends Biochem Sci 20093445363
27 - P Fortugno, A Bresciani, C Paolini, et alProteolytic activation cascade of the Netherton Syndrome-Defective Protein, LEKTI, in the epidermis: implications for skin homeostasis. J Invest Dermatol 2011131222332
28 - M Lacroix, L Lacaze-buzy, L Furio, et alClinical expression and new SPINK5 splicing defects in Netherton syndrome: unmasking a frequent founder synonymous mutation and unconventional intronic mutations.J Invest Dermatol 201213257582
29 - C. A Borgono, I. P Michael, N Komatsu, et alA potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 2007282364052
30 - T Egelrud, M Brattsand, P Kreutzmann, et alhK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br J Dermatol 200515312003
31 - L Furio, A Hovnanian, When activity requires breaking up: LEKTI proteolytic activation cascade for specific proteinase inhibition.J Invest Dermatol 2011131216973
32 - I. S Fernández, L Ständker, H. J Mägert, et alCrystal structure of human epidermal kallikrein 7 (hK7) synthesized directly in its native state in E. coli: insights into the atomic basis of its inhibition by LEKTI domain 6 (LD6)J Mol Biol 2008377148897
33 - T Takeuchi, J. L Harris, W Huang, et alCellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates.J Biol Chem 20002752633342
34 - S. L Lee, R. B Dickson, C. Y Lin, Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease.J Biol Chem 2000275367205
35 - K Nakai, K Yoneda, Y Hosokawa, et alReduced expression of epidermal growth factor receptor, e-cadherin, and occludin in the skin of flaky tail mice is due to filaggrin and loricrin deficiencies.Am J Pathol 201218196977