Department of Medicine, University of Vermont, Burlington, VT, 05405, USA.
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, 05405, USA.
Commun Biol. 2023 Mar 6;6(1):244. doi: 10.1038/s42003-023-04603-w.
Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P-V-L and L-M-S, imparting sensitization and resistance respectively. Unexpectedly, we found several wild-derived inbred strains that carry the resistant HRH1 allotype (L-M-S) but exhibit histamine sensitization. This suggests the existence of a locus modifying pertussis-dependent histamine sensitization. Congenic mapping identified the location of this modifier locus on mouse chromosome 6 within a functional linkage disequilibrium domain encoding multiple loci controlling sensitization to histamine. We utilized interval-specific single-nucleotide polymorphism (SNP) based association testing across laboratory and wild-derived inbred mouse strains and functional prioritization analyses to identify candidate genes for this modifier locus. Atg7, Plxnd1, Tmcc1, Mkrn2, Il17re, Pparg, Lhfpl4, Vgll4, Rho and Syn2 are candidate genes within this modifier locus, which we named Bphse, enhancer of Bordetella pertussis induced histamine sensitization. Taken together, these results identify, using the evolutionarily significant diversity of wild-derived inbred mice, additional genetic mechanisms controlling histamine sensitization.
组氨酸在正常生理中发挥关键作用，组氨酸的产生失调或通过组氨酸受体 (HRH) 信号转导会促进病理学发生。以前，我们发现百日咳博德特氏菌或百日咳毒素可以在实验室近交系小鼠中诱导组氨酸致敏，并且由 Hrh1/HRH1 遗传控制。HRH1 同种型在三个氨基酸残基上存在差异，即 P-V-L 和 L-M-S，分别赋予致敏性和抗性。出乎意料的是，我们发现了几个携带抗性 HRH1 同种型（L-M-S）但表现出组氨酸致敏的野生衍生近交系。这表明存在修饰百日咳依赖性组氨酸致敏的基因座。基因座的共定位作图将其定位在编码多个控制组氨酸致敏的基因座的功能连锁不平衡区域内的小鼠染色体 6 上。我们利用基于间隔特异性单核苷酸多态性 (SNP) 的关联测试，对实验室和野生衍生近交系小鼠进行了测试，并进行了功能优先化分析，以确定该修饰基因座的候选基因。Atg7、Plxnd1、Tmcc1、Mkrn2、Il17re、Pparg、Lhfpl4、Vgll4、Rho 和 Syn2 是该修饰基因座内的候选基因，我们将其命名为 Bphse，增强了百日咳博德特氏菌诱导的组氨酸致敏。总之，这些结果利用野生衍生近交系小鼠的进化重要多样性，确定了控制组氨酸致敏的其他遗传机制。
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