perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”perinatology-102Research ArticleАЛЛЕРГОЛОГИЯALLERGOLOGYКлиническое значение мутаций гена FLG у детей с атопическим дерматитомClinical significance of FLG gene mutations in children with atopic dermatitisВарламовЕ. Е.VarlamovE. E.

к.м.н., с.н.с. отделения аллергологии и клинической иммунологии

ТагироваМ. К.TagirovaM. K.

н.с. лаборатории общей патологии

КомоваЕ. Г.KomovaE. G.

н.с.

ПрасоловаМ. А.PrasolovaM. A.

с.н.с.

ИвановМ. К.IvanovM. K.

начальник лаборатории

СухоруковВ. С.SukhorukovV. S.

д.м.н., проф., зав. лабораторией общей патологии

ПампураА. Н.PampuraA. N.

д.м.н., зав. отделением аллергологии и клинической иммунологии

Научно-исследовательский клинический институт педиатрии ГБОУ ВПО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова», МоскваРоссияResearch Clinical Institute of Pediatrics, N.I. Pirogov Russian National Research Medical University, MoscowRussian FederationЗАО «Вектор-Бест», НовосибирскРоссияZAO «Vector-Best», NovosibirskRussian Federation2015110320166028791Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20162016Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/102

Одним из факторов патогенеза атопического дерматита является нарушение функции кожного барьера вследствие дефекта белка кожи филаггрина. Цель исследования: определить клиническое значение мутаций 2282 del CAGT, R501X, R2447X, S3247X в гене FLG у детей с атопическим дерматитом. В исследование включены 58 детей с атопическим дерматитом. Всем детям проводился молекулярно-генетический анализ четырех мутаций гена FLG. У пациентов с мутациями в гене FLG отмечалась тенденция к увеличению частоты встречаемости сенсибилизации к аллергенам домашней пыли, достоверно чаще наблюдалась сенсибилизация к аллергену эпидермиса кошки, уровень специфических IgE к эпидермису кошки был достоверно выше. Заключение: наличие мутации в гене FLG, кодирующем белок филаггрин, увеличивает риск развития сенсибилизации к бытовым и эпидермальным аллергенам, и в случае уже имеющейся сенсибилизации к эпидермису кошки у пациентов с высокой вероятностью выявляется высокая концентрация специфических IgE к данному аллергену. Указанный факт обосновывает необходимость уделять особое внимание мероприятиям, направленным на элиминацию аллергенов домашней пыли и особенно аллергена эпидермиса кошки и персонализацию подходов к терапии и профилактике атопического дерматита у детей. 

Skin barrier dysfunction due to deficiency of the skin protein filaggrin is one of the factors involved in the pathogenesis of atopic dermatitis. Objective: to determine the clinical significance of 2282 del CAGT, R501X, R2447X, and S3247X mutations in the FLG gene in children with atopic dermatitis. The investigation included 58 children with atopic dermatitis. A molecular genetic analysis of the four mutations in the FLG gene was done in all the children. In the patients with FLG gene mutations, there was a tendency towards a higher frequency of sensitization to house dust allergens, significantly more often sensitization to cat epidermal allergen, and significantly higher levels of specific IgE to the cat epidermis. Conclusion. Mutations in the FLG gene encoding the protein filaggrin raise the risk for sensitization to domestic and epidermal allergens and, in case of already existing sensitization to the cat epidermis, the patients are found with a high degree of probability to have the high concentration of specific IgE to this allergen. The above fact justifies the need to place special emphasis on measures to eliminate house dust allergens, and cat epidermis allergen in particular, and to personalize approaches to therapy and prevention of atopic dermatitis in children. 

детиатопический дерматитбелок филаггринген FLGchildrenatopic dermatitisprotein filaggrinFLG geneReferencesWilliams H., Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol 2006; 118: 1: 209—213.Williams H., Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol 2006; 118: 1: 209—213.Novak N., Leung D.Y. Advances in atopic dermatitis. Curr Opin Immunol 2011; 23: 6: 778—783.Novak N., Leung D.Y. Advances in atopic dermatitis. Curr Opin Immunol 2011; 23: 6: 778—783.Weidinger S., Illig T., Baurecht H. et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006; 118: 1: 214—219.Weidinger S., Illig T., Baurecht H. et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006; 118: 1: 214—219.Nomura T., Sandilands A., Akiyama M. et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 2007; 119: 2: 434—440.Nomura T., Sandilands A., Akiyama M. et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 2007; 119: 2: 434—440.Kolbe L., Kligman A.M., Schreiner V., Stoudemayer T. Corticosteroid- induced atrophy and barrier impairment measured by non-invasive methods in human skin. Skin Res Technol 2001; 7: 2: 73—77.Kolbe L., Kligman A.M., Schreiner V., Stoudemayer T. Corticosteroid- induced atrophy and barrier impairment measured by non-invasive methods in human skin. Skin Res Technol 2001; 7: 2: 73—77.Nemoto-Hasebe I., Akiyama M., Nomura T. et al. Clinical Severity Correlates with Impaired Barrier in Filaggrin-Related Eczema. Journal of Investigative Dermatology 2009; 129: 3: 682—689.Nemoto-Hasebe I., Akiyama M., Nomura T. et al. Clinical Severity Correlates with Impaired Barrier in Filaggrin-Related Eczema. Journal of Investigative Dermatology 2009; 129: 3: 682—689.Киндеева Е.Т., Варламов Е.Е., Пампура А.Н. Функциональное состояние кожного барьера у детей с атопическим дерматитом. Рос аллергологический журн 2013; 1: 52—57. (Kindeeva E.T., Varlamov E.E., Pampura A.N. The functional state of the skin bаrrier at children with atopic dermatitis. Ros allergologicheskij zhurn 2013; 1: 52—57.)Киндеева Е.Т., Варламов Е.Е., Пампура А.Н. Функциональное состояние кожного барьера у детей с атопическим дерматитом. Рос аллергологический журн 2013; 1: 52—57. (Kindeeva E.T., Varlamov E.E., Pampura A.N. The functional state of the skin bаrrier at children with atopic dermatitis. Ros allergologicheskij zhurn 2013; 1: 52—57.)Elias P. Feingold K. Skin Barrier. New York, London. Informa Healthcare, 2005; 632.Elias P. Feingold K. Skin Barrier. New York, London. Informa Healthcare, 2005; 632.Kamata Y., Taniguchi A., Yamamoto M. et al. Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids. J Biol Chem 2009; 284: 19: 12829—12836.Kamata Y., Taniguchi A., Yamamoto M. et al. Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids. J Biol Chem 2009; 284: 19: 12829—12836.Rawlings A.V., Harding C.R. Moisturization and skin barrier function. Dermatol 2004; 17: 1: 43—48.Rawlings A.V., Harding C.R. Moisturization and skin barrier function. Dermatol 2004; 17: 1: 43—48.Krien P., Kermici M. Evidence for the existence of a self-regulated enzymatic process within human stratum corneum-an unexpected role for urocanic acid. J Invest Dermatol 2000; 115: 3: 414—420.Krien P., Kermici M. Evidence for the existence of a self-regulated enzymatic process within human stratum corneum-an unexpected role for urocanic acid. J Invest Dermatol 2000; 115: 3: 414—420.Schmid-Wendtner M.H., Korting H.C. The pH of the skin surface and its impact on the barrier function. Skin Pharmcol Physiol 2006; 19: 6: 296—302.Schmid-Wendtner M.H., Korting H.C. The pH of the skin surface and its impact on the barrier function. Skin Pharmcol Physiol 2006; 19: 6: 296—302.Elias P.M., Hatano Y., Williams M.L. Basis for the barrier abnormality in atopic dermatitis. J Allergy Clin Immunol 2008; 121: 6: 1337—1343.Elias P.M., Hatano Y., Williams M.L. Basis for the barrier abnormality in atopic dermatitis. J Allergy Clin Immunol 2008; 121: 6: 1337—1343.Morar N., Cookson W., Harper J. et al. Filaggrin Mutations in Children with Severe Atopic Dermatitis. J of Investigative Dermatol 2007; 127: 7: 1667—1672.Morar N., Cookson W., Harper J. et al. Filaggrin Mutations in Children with Severe Atopic Dermatitis. J of Investigative Dermatol 2007; 127: 7: 1667—1672.Barker J.N.W.N., Palmer C.N.A., Zhao Y. et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol 2007; 127: 3: 564—567.Barker J.N.W.N., Palmer C.N.A., Zhao Y. et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol 2007; 127: 3: 564—567.Weidinger S. Rodrıguez E., Stahl C. et al. Filaggrin Mutations Strongly Predispose to Early-Onset and Extrinsic Atopic Dermatitis. Journal of Investigative Dermatology 2007; 127: 3: 724—726.Weidinger S. Rodrıguez E., Stahl C. et al. Filaggrin Mutations Strongly Predispose to Early-Onset and Extrinsic Atopic Dermatitis. Journal of Investigative Dermatology 2007; 127: 3: 724—726.Brown S., Relton C.L., Liao H. et al. Filaggrin null mutations and childhood atopic eczema: A population-based case-control study. J Allergy Clin Immunol 2008; 121: 4: 940—946.Brown S., Relton C.L., Liao H. et al. Filaggrin null mutations and childhood atopic eczema: A population-based case-control study. J Allergy Clin Immunol 2008; 121: 4: 940—946.Brown S.J., Relton C.L., Liao H. et al. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br J Dermatol 2009; 161: 4: 884—889.Brown S.J., Relton C.L., Liao H. et al. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br J Dermatol 2009; 161: 4: 884—889.Hanifin J.M., Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venerol (Stock) 1980; 92: 44—47.Hanifin J.M., Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venerol (Stock) 1980; 92: 44—47.Национальная программа «Бронхиальная астма у детей. Стратегия лечения и профилактика». М: Атмосфера 2008; 108. (The National Program «Asthma in children. Strategy and prevention». M: Atmosphera 2008; 108.)Национальная программа «Бронхиальная астма у детей. Стратегия лечения и профилактика». М: Атмосфера 2008; 108. (The National Program «Asthma in children. Strategy and prevention». M: Atmosphera 2008; 108.)Eichenfield L.F., Hanifin C.J., Luger T.A. et al. Consensus Conference on Pediatric Atopic Dermatitis. J Am Acad Dermatol 2003; 49: 6: 1088—1095.Eichenfield L.F., Hanifin C.J., Luger T.A. et al. Consensus Conference on Pediatric Atopic Dermatitis. J Am Acad Dermatol 2003; 49: 6: 1088—1095.Prasolova M.A., Shchepotina E.G., Dymshits G.M. Development of a high-throughput fluorescence assay for detecting SNPs in hemostasis and folate metabolism genes for clinical Use. Mol Genet microbiol Virol 2013; 28: 1: 24—31.Prasolova M.A., Shchepotina E.G., Dymshits G.M. Development of a high-throughput fluorescence assay for detecting SNPs in hemostasis and folate metabolism genes for clinical Use. Mol Genet microbiol Virol 2013; 28: 1: 24—31.Palmer C.N, Irvine A.D., Terron-Kwiatkowski A. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 4: 441—446.Palmer C.N, Irvine A.D., Terron-Kwiatkowski A. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 4: 441—446.Irvine A.D. Fleshing Out Filaggrin Phenotypes. Journal of Investigative Dermatology 2007; 127: 3: 504—507.Irvine A.D. Fleshing Out Filaggrin Phenotypes. Journal of Investigative Dermatology 2007; 127: 3: 504—507.Komova E.G., Shintyapina A.V., Makarova S.I. et al. Filaggrin mutations in a Western Siberian population and their association with atopic dermatitis in children. Genet Test Mol Biomarkers 2014; 18: 12: 791—796.Komova E.G., Shintyapina A.V., Makarova S.I. et al. Filaggrin mutations in a Western Siberian population and their association with atopic dermatitis in children. Genet Test Mol Biomarkers 2014; 18: 12: 791—796.Bisgaard H., Simpson A., Colin N.A. et al. Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Lossof- Function Mutations Enhanced by Neonatal Cat Exposure. PLoS Medicine 2008; 5: 6: 131.Bisgaard H., Simpson A., Colin N.A. et al. Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Lossof- Function Mutations Enhanced by Neonatal Cat Exposure. PLoS Medicine 2008; 5: 6: 131.Henderson J., Northstone K., Lee S. et al. The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study. J Allergy Clin Immunol 2008; 121: 4: 872—877.Henderson J., Northstone K., Lee S. et al. The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study. J Allergy Clin Immunol 2008; 121: 4: 872—877.

The authors declare that there are no conflicts of interest present.