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Dominant atopy risk mutations identified by mouse forward genetic analysis

机译:鼠标前瞻性遗传分析鉴定的显性特性风险突变

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摘要

Background Atopy, the overall tendency to become sensitized to an allergen, is heritable but seldom ascribed to mutations within specific genes. Atopic individuals develop abnormally elevated IgE responses to immunization with potential allergens. To gain insight into the genetic causes of atopy, we carried out a forward genetic screen for atopy in mice. Methods We screened mice carrying homozygous and heterozygousN-ethyl-N-nitrosourea (ENU)-induced germline mutations for aberrant antigen-specific IgE and IgG1 production in response to immunization with the model allergen papain. Candidate genes were validated by independent gene mutation. Results Of 31 candidate genes selected for investigation, the effects of mutations in 23 genes on papain-specific IgE or IgG1 were verified. Among the 20 verified genes influencing the IgE response, eight were necessary for the response, while 12 repressed IgE. Nine genes were not previously implicated in the IgE response. Fifteen genes encoded proteins contributing to IgE class switch recombination or B-cell receptor signaling. The precise roles of the five remaining genes (Flcn, Map1lc3b, Me2,Prkd2,andScarb2) remain to be determined. Loss-of-function mutations in nine of the 12 genes limiting the IgE response were dominant or semi-dominant for the IgE phenotype but did not cause immunodeficiency in the heterozygous state. Using damaging allele frequencies for the corresponding human genes and in silico simulations (Monte Carlo) of undiscovered atopy mutations, we estimated the percentage of humans with heterozygous atopy risk mutations. Conclusions Up to 37% of individuals may be heterozygous carriers for at least one dominant atopy risk mutation.
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  • 来源
    《Allergy》 |2021年第4期|共14页
  • 作者单位

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

    Univ Texas Southwestern Med Ctr Dallas Ctr Genet Host Def 5323 Harry Hines Blvd Dallas TX 75390;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学免疫学;
  • 关键词

    allergy; atopy; IgE; IgG1; papain;

    机译:过敏;特性;IgE;IgG1;木瓜;

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