J Korean Med Sci.  2016 Jul;31(7):1136-1142. 10.3346/jkms.2016.31.7.1136.

An Analysis of the Filaggrin Gene Polymorphism in Korean Atopic Dermatitis Patients

• Park KY
• Li K
• Seok J
• Seo SJ

• KMID: 2373735
• DOI: http://doi.org/10.3346/jkms.2016.31.7.1136

Abstract

Research of the FLG mutation in various ethnic groups revealed non-overlapping mutation patterns. In addition, Japanese and Chinese atopic patients showed somewhat different mutations. These ethnic differences make the research on Korean patients mandatory; however, no systematic research on Korean atopic dermatitis (AD) patients has been performed. This study aims to investigate the genetic polymorphism of FLG in Korean atopic dermatitis patients. The study was made up of three groups including 9 Ichthyosis vulgaris (IV) patients, 50 AD patients and 55 normal controls: the ichthyosis group was incorporated due to the reported association between the FLG mutation and IV. In comparison to other sequencing methods, the overlapping long-range PCR was used. We revealed the genetic polymorphism of filaggrin in Koreans, and at the same time, we discovered nonsense mutations in p.Y1767X and p.K4022X in Korean AD patients. By using FLG sequencing techniques confirmed in this study, new mutations or genetic polymorphisms with ethnic characteristics would be detected and further larger studies of repeat number polymorphisms could be performed.

Keyword

Atopic Dermatitis; Filaggrin; Genetic Polymorphism; Ichthyosis Vulgaris; Korean; Sequence Analysis

MeSH Terms

Adult
Alleles
Asian Continental Ancestry Group/*genetics
Base Sequence
Codon, Nonsense
DNA/blood/chemistry/metabolism
DNA Mutational Analysis
Dermatitis, Atopic/*genetics
Female
Genotype
Heterozygote
Humans
Ichthyosis Vulgaris/genetics
Intermediate Filament Proteins/*genetics
Male
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Codon, Nonsense
DNA
Intermediate Filament Proteins

Figure

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  Fig. 1 Strategy used in this study for mutation detection for FLG. Newly designed DNA fragments are indicated by red color. As shown in the results of electrophoresis, most DNA fragments were successfully amplified.

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  Fig. 2 Novel mutation p.Y1767X in Korean ichthyosis vulgaris family. Also note the known mutation, p.K4022X, in the mother and the index case. Each quadrant was assigned to represent phenotypes. IV, ichthyosis vulgaris; AD, atopic dermatitis; AS, asthma; AR, allergic rhinitis.

Reference

1. Dale BA, Presland RB, Lewis SP, Underwood RA, Fleckman P. Transient expression of epidermal filaggrin in cultured cells causes collapse of intermediate filament networks with alteration of cell shape and nuclear integrity. J Invest Dermatol. 1997; 108:179–187.

2. 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.

3. Gruber R, Elias PM, Crumrine D, Lin TK, Brandner JM, Hachem JP, Presland RB, Fleckman P, Janecke AR, Sandilands A, et al. Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function. Am J Pathol. 2011; 178:2252–2263.

4. Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kezic S, Cordell HJ, McLean WH, Irvine AD. Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect. J Invest Dermatol. 2012; 132:98–104.

5. Gan SQ, McBride OW, Idler WW, Markova N, Steinert PM. Organization, structure, and polymorphisms of the human profilaggrin gene. Biochemistry. 1990; 29:9432–9440.

6. Ginger RS, Blachford S, Rowland J, Rowson M, Harding CR. Filaggrin repeat number polymorphism is associated with a dry skin phenotype. Arch Dermatol Res. 2005; 297:235–241.

7. McGrath JA, Uitto J. The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol Med. 2008; 14:20–27.

8. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006; 38:337–342.

9. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006; 38:441–446.

10. Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, Allen MH, Meggitt SJ, Reynolds NJ, Trembath RC, 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; 127:564–567.

11. Flohr C, England K, Radulovic S, McLean WH, Campbel LE, Barker J, Perkin M, Lack G. Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age. Br J Dermatol. 2010; 163:1333–1336.

12. van den Oord RA, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ. 2009; 339:b2433.

13. Hsu CK, Akiyama M, Shimizu H. Filaggrin: an emerging star in atopic march. J Formos Med Assoc. 2008; 107:429–431.

14. Akiyama M. FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics. Br J Dermatol. 2010; 162:472–477.

15. Park J, Jekarl DW, Kim Y, Kim J, Kim M, Park YM. Novel FLG null mutations in Korean patients with atopic dermatitis and comparison of the mutational spectra in Asian populations. J Dermatol. 2015; 42:867–873.

16. Kang TW, Lee JS, Oh SW, Kim SC. Filaggrin mutation c.3321delA in a Korean patient with ichthyosis vulgaris and atopic dermatitis. Dermatology. 2009; 218:186–187.

17. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007; 39:650–654.

18. Sasaki T, Kudoh J, Ebihara T, Shiohama A, Asakawa S, Shimizu A, Takayanagi A, Dekio I, Sadahira C, Amagai M, et al. Sequence analysis of filaggrin gene by novel shotgun method in Japanese atopic dermatitis. J Dermatol Sci. 2008; 51:113–120.

19. Kim EJ, Jeong MS, Li K, Park MK, Lee MK, Yoon Y, Cho DY, Seo SJ. Genetic polymorphism of FLG in Korean ichthyosis vulgaris patients. Ann Dermatol. 2011; 23:170–176.

20. Nemoto-Hasebe I, Akiyama M, Nomura T, Sandilands A, McLean WH, Shimizu H. FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema. Br J Dermatol. 2009; 161:1387–1390.

21. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003; 112:S118–27.

22. McKinley-Grant LJ, Idler WW, Bernstein IA, Parry DA, Cannizzaro L, Croce CM, Huebner K, Lessin SR, Steinert PM. Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21. Proc Natl Acad Sci USA. 1989; 86:4848–4852.

23. Li M, Cheng R, Shi M, Liu J, Zhang G, Liu Q, Yu H, Yao Z. Analyses of FLG mutation frequency and filaggrin expression in isolated ichthyosis vulgaris (IV) and atopic dermatitis-associated IV. Br J Dermatol. 2013; 168:1335–1338.

24. Cascella R, Foti Cuzzola V, Lepre T, Galli E, Moschese V, Chini L, Mazzanti C, Fortugno P, Novelli G, Giardina E. Full sequencing of the FLG gene in Italian patients with atopic eczema: evidence of new mutations, but lack of an association. J Invest Dermatol. 2011; 131:982–984.