Dominant atopy risk mutations identified by mouse forward genetic analysis

Jeffrey A. SoRelle, Zhe Chen, Jianhui Wang, Tao Yue, Jin Huk Choi, Kuan wen Wang, Xue Zhong, Sara Hildebrand, Jamie Russell, Lindsay Scott, Darui Xu, Xiaowei Zhan, Chun Hui Bu, Tao Wang, Mihwa Choi, Miao Tang, Sara Ludwig, Xiaoming Zhan, Xiaohong Li, Eva Marie Y. MorescoBruce Beutler

Research output: Contribution to journalArticlepeer-review

Abstract

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 heterozygous N-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, and Scarb2) 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.

Original languageEnglish (US)
Pages (from-to)1095-1108
Number of pages14
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume76
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • IgE
  • IgG1
  • allergy
  • atopy
  • papain

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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