Naturally Occurring Missense MRGPRX2 Variants Display Loss of Function Phenotype for Mast Cell Degranulation in Response to Substance P, Hemokinin-1, Human B-Defensin-3, and Icatibant

Thumbnail Image
Penn collection
Departmental Papers (Dental)
Degree type
Animals; beta-Defensins; Bradykinin; Cell Degranulation; Cell Line
Tumor; Humans; Ligands; Loss of Function Mutation; Mast Cells; Mutation
Missense; Nerve Tissue Proteins; Neuropeptides; Phenotype; Rats; Receptors
G-Protein-Coupled; Receptors
Neuropeptide; Substance P; Tachykinins
Grant number
Copyright date
Related resources
Alkanfari, I.
Gupta, K.
Jahan, T.
Ali, H.

Human mast cells (MCs) express a novel G protein–coupled receptor (GPCR) known as Mas-related GPCR X2 (MRGPRX2). Activation of this receptor by a diverse group of cationic ligands such as neuropeptides, host defense peptides, and Food and Drug Administration–approved drugs contributes to chronic inflammatory diseases and pseudoallergic drug reactions. For most GPCRs, the extracellular (ECL) domains and their associated transmembrane (TM) domains display the greatest structural diversity and are responsible for binding different ligands. The goal of the current study was to determine if naturally occurring missense variants within MRGPRX2’s ECL/TM domains contribute to gain or loss of function phenotype for MC degranulation in response to neuropeptides (substance P and hemokinin-1), a host defense peptide (human b-defensin-3) and a Food and Drug Administration–approved cationic drug (bradykinin B2 receptor antagonist, icatibant). We have identified eight missense variants within MRGPRX2’s ECL/TM domains from publicly available exome-sequencing databases. We investigated the ability of MRGPRX2 ligands to induce degranulation in rat basophilic leukemia–2H3 cells individually expressing these naturally occurring MRGPRX2 missense variants. Using stable and transient transfections, we found that all variants express in rat basophilic leukemia cells. However, four natural MRGPRX2 variants, G165E (rs141744602), D184H (rs372988289), W243R (rs150365137), and H259Y (rs140862085) failed to respond to any of the ligands tested. Thus, diverse MRGPRX2 ligands use common sites on the receptor to induce MC degranulation. These findings have important clinical implications for MRGPRX2 and MC-mediated pseudoallergy and chronic inflammatory diseases. Copyright © 2018 by The American Association of Immunologists, Inc.

Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Publication date
Journal title
Journal of Immunology
Volume number
Issue number
Publisher DOI
Journal Issue
Recommended citation