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FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema

Authors

  • I. Nemoto-Hasebe,

    1. Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • M. Akiyama,

    1. Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • T. Nomura,

    1. Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
    2. Epithelial Genetics Group, Division of Molecular Medicine, University of Dundee, Colleges of Life Sciences and Medicine, Dentistry & Nursing, Dundee, U.K.
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  • A. Sandilands,

    1. Epithelial Genetics Group, Division of Molecular Medicine, University of Dundee, Colleges of Life Sciences and Medicine, Dentistry & Nursing, Dundee, U.K.
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  • W.H.I. McLean,

    1. Epithelial Genetics Group, Division of Molecular Medicine, University of Dundee, Colleges of Life Sciences and Medicine, Dentistry & Nursing, Dundee, U.K.
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  • H. Shimizu

    1. Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • Conflicts of interest
    W.H.I.M. has filed patents relating to genetic testing and therapy development aimed at the filaggrin gene.

Masashi Akiyama.
E-mail: akiyama@med.hokudai.ac.jp

Summary

Background  Mutations in the gene encoding filaggrin (FLG) have been shown to predispose to atopic eczema (AE).

Objectives  Further to establish population genetics of FLG mutations in the Japanese population and to elucidate effects of FLG mutations to filaggrin biosynthesis in skin of patients with AE.

Methods  We searched for FLG mutations in 19 newly recruited Japanese patients with AE. We then screened 137 Japanese patients with AE and 134 Japanese control individuals for a novel mutation identified in the present study. In addition, we evaluated FLG mRNA expression by real-time reverse transcription–polymerase chain reaction and profilaggrin/filaggrin protein expression by immunohistochemical staining in the epidermis of the patients carrying the novel mutation.

Results  We identified a novel FLG nonsense mutation c.12069A>T (p.Lys4021X) in one patient with AE. Upon further screening, p.Lys4021X was identified in four patients with AE (2·9% of all the patients with AE). In total, there are at least eight FLG variants in the Japanese population. Here we show that about 27% of patients in our Japanese AE case series carry one or more of these eight FLG mutations and these variants are also carried by 3·7% of Japanese general control individuals. There is a significant statistical association between the eight FLG mutations and AE (χ2P = 6·50 × 10−8). Interestingly, the present nonsense mutation is in the C-terminal incomplete filaggrin repeat and is the mutation nearest the C-terminal among previously reported FLG mutations. Immunohistochemical staining for filaggrin revealed that this nonsense mutation leads to remarkable reduction of filaggrin protein expression in the patients’ epidermis.

Conclusions  We clearly demonstrated that FLG mutations are significantly associated with AE in the Japanese population. The present results further support the hypothesis that the C-terminal region is essential for proper processing of profilaggrin to filaggrin.

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