Dominant atopy risk mutations identified by mouse forward genetic analysis. Issue 4 (20th September 2020)

• Record Type: Journal Article
• Authors: SoRelle, Jeffrey A.; Chen, Zhe; Wang, Jianhui; Yue, Tao; Choi, Jin Huk; Wang, Kuan‐wen; Zhong, Xue; Hildebrand, Sara; Russell, Jamie; Scott, Lindsay; Xu, Darui; Zhan, Xiaowei; Bu, Chun Hui; Wang, Tao; Choi, Mihwa; Tang, Miao; Ludwig, Sara; Zhan, Xiaoming; Li, Xiaohong; Moresco, Eva Marie Y.; Beutler, Bruce
• Is Part Of: Allergy. Volume 76:Issue 4(2021)
• Page Start: 1095
• Page End: 1108
• Publication Date: 2020-09-20
• Subjects: allergy -- atopy -- IgE -- IgG1 -- papain; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.14564
• Languages: English
• ISSNs: 0105-4538

Abstract

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, Map1 lc3b, 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. Abstract : This study uses a classical genetic screen employing automated meiotic mapping of pregenotyped mice and CRISPR/Cas9‐based verification to identify numerous mutations causing altered IgE responses to papain immunization. Three‐quarters of mutations that increased allergen‐specific IgE are dominant or semidominant, without causing immunodeficiency in the heterozygous state. Up to 37% of immunocompetent humans may carry a heterozygous, dominant atopy risk mutation. Abbreviations: CRISPR, clustered regularly interspaced short palindromic repeats; ENU, N ‐ethyl‐ N ‐nitrosourea.