Background: It is assumed that beside alterations in the filaggrin gene (FLG), disturbances within genes encoding other cornified envelope proteins are also involved in atopic dermatitis (AD). To identify new potential markers of AD, we studied the polymorphisms of genes encoding repetin (RPTN), cornulin (CRNN), and their expression in the skin of AD patients. Methods: Polymorphisms in CRNN (rs941934), RPTN (rs284544, rs28441202, rs3001978, and rs12117644), and FLG mutations (R2447X, S3247X) were analyzed by TaqMan genotyping assay and by PCR-RFLP in the blood samples of 159 AD patients and 108 healthy subjects. The expression levels of CRNN and RPTN were determined by qRT-PCR in 34 AD skin samples (17 lesional and 17 nonlesional) and in 27 skin biopsies from healthy volunteers. The AD patients were recruited from the clinic of the university hospital between 2012 and 2014. Results:CRNN rs941934 (A allele) was associated with AD (OR 2.095, p = 0.008), a severe course of disease (p = 0.041), elevated IgE levels (p = 0.047), eosinophilia (p = 0.018), and concomitant asthma (p = 0.004). The mRNA level of CRNN was decreased in the AD skin (p = 0.041). In the AD patients without FLG mutations, the CC genotype of RPTN rs3001978 was associated with AD (OR 0.39, p = 0.037), early age at onset (p = 0.033), pruritus (p = 0.021), severity of AD (p = 0.045), and concomitant asthma (p = 0.041). The elevated mRNA levels of RPTN in lesional (p < 0.001) and nonlesional (p = 0.017) AD skin were observed. Conclusions: The single-nucleotide polymorphisms of CRNN (rs941934) and RPTN (rs3001978, rs28441202) may contribute to AD development, but further studies on a larger group of AD patients are needed to verify this assumption.

Peng W, Novak N: Pathogenesis of atopic dermatitis. Clin Exp Allergy 2015;45:566-574.
Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB Jr, Manuel JC: The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol 2005;22:192-199.
DaVeiga SP: Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc 2012;33:227-234.
Bieber T: Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012;67:1475-1482.
Leung DY: New insights into atopic dermatitis: role of skin barrier and immune dysregulation. Allergol Int 2013;62:151-161.
Babić Z, Sabolić Pipinić I, Varnai V.M, Kežić S, Macan J: Associations of TNFα -308G>A, TNFα -238G>A, IL-1α -889C>T and IL-10 -1082G>A genetic polymorphisms with atopic diseases: asthma, rhinitis and dermatitis. Int Arch Allergy Immunol 2016;169:231-240.
Elias PM, Wakefield JS: Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis. Allergy Clin Immunol 2014;134:781-791.
van Smeden J, Janssens M, Kaye EC, Caspers PJ, Lavrijsen AP, Vreeken RJ, Bouwstra JA: The importance of free fatty acid chain length for the skin barrier function in atopic eczema patients. Exp Dermatol 2014:23:45-52.
Henry J, Toulza E, Hsu CY, Pellerin L, Balica S, Mazereeuw-Hautier J, Paul C, Serre G, Jonca N, Simon M: Update on the epidermal differentiation complex. Front Biosci 2012;17:1517-1532.
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeat A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441-446.
Palmer, Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, Janecke AR, Elias PM, van Steensel MA, Nagtzaam I, van Geel M, Steijlen PM, Munro CS, Bradley DG, Palmer CN, Smith FJ, McLean WH, Irvine AD: Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007;39:650-654.
Guttman-Yassky E, Suarez-Farinas M, Chiricozzi A, Nograles KE, Shemer A, Fuentes-Duculan J, Cardinale I, Lin P, Bergman R, Bowcock AM, Krueger JG: Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol 2009;124:1235-1244.
Thyssen JP, Godoy-Gijon E, Elias PM: Ichthyosis vulgaris: the filaggrin mutation disease. Br J Dermatol 2013;168:1155- 1166.
Margolis DJ, Gupta J, Apter AJ, Ganguly T, Hoffstad O, Papadopoulos M, Rebbeck TR, Mitra N: Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects. J Allergy Clin Immunol 2014;133:784-789.
Lapp T, Auw-Haedrich C, Reinhard T, Evans R, Rodríguez E, Weidinger S, Jakob T: Analysis of filaggrin mutations and expression in corneal specimens from patients with or without atopic dermatitis. Int Arch Allergy Immunol 2014;163:20-24.
Ziyab AH, Karmaus W, Zhang H, Holloway JW, Steck SE, Ewart S, Arshad SH: Association of filaggrin variants with asthma and rhinitis: is eczema or allergic sensitization status an effect modifier? Int Arch Allergy Immunol 2014;164:308-318.
Thyssen JP, Kezic S: Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 2014;134:792-799.
Jakasa I, Koster ES, Calkoen F, McLean WH, Campbell LE, Bos JD, Verberk MM, Kezic S: Skin barrier function in healthy subjects and patients with atopic dermatitis in relation to filaggrin loss-of-function mutations. J Invest Dermatol 2011;131:540-542.
de Koning HD, van den Bogaard EH, Bergboer JG, Kamsteeg M, van Vlijmen-Willems IM, et al: Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair. Br J Dermatol 2012;166:1245-1254.
Trzeciak M, Sakowicz-Burkiewicz M, Wesserling M, Dobaczewska D, Glen J, Nowicki R, Pawelczyk T: Expression of cornified envelope proteins in skin and its relationship with atopic dermatitis phenotype. Acta Derm Venereol 2016, E-pub ahead of print.
Esparza-Gordillo J, Weidinger S, Fölster-Holst R, Bauerfeind A, Ruschendorf F, et al: A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 2009;41:596-601.
Sugiura, H, Ebise H, Tazawa T, Tanaka K, Sugiura Y, Uehara M, Kikuchi K, Kimura T: Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br J Dermatol 2005;152:146-149.
Liedén A, Ekelund E, Kuo IC, Kockum I, Huang CH, Mallbris L, Lee SP, Seng LK, Chin GY, Wahlgren CF, Palmer CN, Björkstén B, Ståhle M, Nordenskjöld M, Bradley M, Chua KY, D'Amato M: Cornulin, a marker of late epidermal differentiation, is down-regulated in eczema. Allergy 2009;64:304-311.
Sharma M, Mehla K, Batra J, Ghosh B: Association of a chromosome 1q21 locus in close proximity to a late cornified envelope-like proline-rich 1 (LELP1) gene with total serum IgE levels. J Hum Genet 2007;52:378-383.
Trzeciak M, Wesserling M, Bandurski T, Glen J, Nowicki R, Pawelczyk T: Association of a single nucleotide polymorphism in a late cornified envelope-like proline-rich 1 gene with atopic dermatitis. Acta Derm Venereol 2016;96:459-463.
Kligman D, Hilt DC: The S100 protein family. Trends Biochem Sci 1988;13:437-443.
Contzler R, Favre B, Huber M, Hohl D: Cornulin, a new member of the “fused gene” family, is expressed during epidermal differentiation. J Invest Dermatol 2005;124:990-997.
Huber M, Siegenthaler G, Mirancea N, Abecasis GR, Walley AJ, Cox HE, Coleman R, Leaves NI, Trembath RC, Moffatt MF, Harper JI: Isolation and characterization of human repetin, a member of the fused gene family of the epidermal differentiation complex. J Invest Dermatol 2005;124:998-1007.
Segre JA, Bauer C, Fuchs E: Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet 1999;22:356-360.
Koch PJ, de Viragh PA, Scharer E, Bundman D, Longley MA, Bickenbach J, Kawachi Y, Suga Y, Zhou Z, Huber M, Hohl D, Kartasova T, Jarnik M, Steven AC, Roop DR: Lessons from loricrin-deficient mice: compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein. J Cell Biol 2000;16;151:389-400.
Otsuka A, Doi H, Egawa G, Maekawa A, Fujita T, Nakamizo S, Nakashima C, Nakajima S, Watanabe T, Miyachi Y, Narumiya S, Kabashima K: Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression. J Allergy Clin Immunol 2014;133:139-146.
Hanifin JM, Rajka G: Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980;59:44-47.
Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-159.
Excoffier L, Laval G, Schneider S: Arlequin v3.1: an integrated software package for population genetics data analysis. Evol Bioinform Online 2005;1:47-50.
Cookson WO, Ubhi B, Lawrence R et al: Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001;27:372-373.
Chen K, Li Y, Dai Y, Li J, Qin Y, Zhu Y, Zeng T, Ban X, Fu L, Guan XY: Characterization of tumor suppressive function of cornulin in esophageal squamous cell carcinoma. PLoS One 2013;8:e68838.
Tyszkiewicz T, Jarzab M, Szymczyk C, Kowal M, Krajewska J, Jaworska M, Fraczek M, Krajewska A, Hadas E, Swierniak M, Markowski J, Lange D, Poltorak S, Wiench M, Krecicki T, Jarzab J, Maciejewski A: Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa. Folia Histochem Cytobiol 2014;52:79-89.
Jensen AO, Svaerke C, Körmendiné Farkas D, Olesen AB, Kragballe K, Sørensen HT: Atopic dermatitis and risk of skin cancer: a Danish nationwide cohort study (1977-2006). Am J Clin Dermatol 2012;13:29-36.
Cheng J, Zens MS, Duell E, Perry AE, Chapman MS, Karagas MR: History of allergy and atopic dermatitis in relation to squamous cell and basal cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev 2015;24:749-754.
Sääf AM, Tengvall-Linder M, Chang HY, Adler AS, Wahlgren CF, Scheynius A, Nordenskjöld M, Bradley M: Global expression profiling in atopic eczema reveals reciprocal expression of inflammatory and lipid genes. PLoS One 2008;3:e4017.
Liedén A, Winge MC, Sääf A, Kockum I, Ekelund E, Rodriguez E, Fölster-Holst R, Franke A, Illig T, Tengvall-Linder M, Baurecht H, Weidinger S, Wahlgren CF, Nordenskjöld M, Bradley M: Genetic variation in the epidermal transglutaminase genes is not associated with atopic dermatitis. PLoS One 2012;7:e49694.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.