Genetic analysis of Bphse and Shs, novel loci controlling hypersensitivity to histamine in mice

Abstract

Abstract Histamine (HA) is a biogenic amine produced by mast cells and basophils that regulates many physiological processes including acute and chronic inflammation, immune regulation, and immediate hypersensitivity reactions. Previously, we mapped Bphs, the autosomal dominant locus in mice controlling hypersensitivity to HA following exposure to either Bordetella pertussis or pertussis toxin (PTX) to chromosome 6 (Chr6). Positional candidate gene cloning identified Bphs as HA H1 receptor (Hrh1/H1R). The Bphs-susceptible H1R allele possesses the Pro263, Val312 and Pro330 haplotype while the Bphs-resistant H1R allele have the Leu263, Met312 and Ser330 haplotype. Unexpectedly, when we tested a panel of inbred wild-derived strains for Bphs, we discovered strains e.g. MOLF/EiJ, that are phenotypically Bphs-susceptible despite carrying the resistant H1R allele. Phylogenetically, these strains are confined to a unique branch of wild-derived strains. This supports the existence of an evolutionary selected mechanism capable of complementing Hrh1resistance. Linkage analysis mapped the locus to Chr6, in linkage disequilibrium (LD) with Hrh1. We have designated this locus Bphs-enhancer (Bphse). Additionally, we identified a second Hrh1-linked gene in aged and CFA immunized SJL/J mice controlling HA hypersensitivity in the absence of Bordetella pertussis/PTX-sensitization. We have designated this spontaneous histamine sensitivity (Shs/Shs). Taken together, these data support the existence of a LD domain harboring multiple genes that control hypersensitivity to HA. The identification of the genes underlying both Bphse and Shs has the potential to significantly extend our understanding of the genetic control of HA signaling.