C1ORF150 regulation of human mast cell activation - urticaria ("hives") is a significant health concern, affecting 20% of individuals over their lifetime

The National Institute of Allergy and Infectious Diseases awarded the University of New Hampshire $244,410 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of the C1ORF150 protein in mast cell activation and chronic urticaria.

Chronic urticaria affects approximately 800,000 individuals in the U.S. and persists for more than six weeks, with 30–50 percent of patients failing to respond to standard anti-histamine and anti-IgE monoclonal antibody therapies. Genome-wide association studies identified a donor-acceptor splice variant at the C1ORF150 locus as a significant urticaria-associated genetic marker. The variant produces an altered protein isoform lacking an N-terminal 20-amino-acid domain. The research will test the hypothesis that the full-length C1ORF150 protein normally suppresses mast cell activation and degranulation, while the truncated isoform impairs this suppression through compromised interaction with co-effector proteins at key receptor ligation sites (FCER1, MRGPRX2, and KIT). The work involves ectopic expression of both full-length C1ORF150 and the C1ORF150-EXON2 isoform in LAD2 cells and human induced pluripotent stem cell-derived mast cells to characterize effects on ligand-induced degranulation and receptor-mediated mast cell activation.

The award is a Project Grant with a period of performance from September 1, 2026, through August 31, 2028. Performance occurs in New Hampshire.

Chronic urticaria ("CU") is persistent (>6 weeks, and 2-5 years on average) and affects ~800,000 in the US. Critically, 30-50% of CU patients fail to respond to standard therapies (anti-histamines, anti-IGE MAB), resulting in impaired quality of life and substantial national healthcare costs. Recent gwas studies have identified the donor-acceptor splice variant C1ORF150 [RS56043070(a)] as a new, and most significant CU- associated locus. This variant is associated with multiple urticaria markers, but unlike other urticaria associated loci is not associated with elevated serum IGE. At the C1ORF150 [RS56043070(a)] locus, this variant encodes an mrna in which exon-2 is selectively excised in-frame. Upon translation, this alternate transcript encodes an altered protein isoform (termed "C1ORF150-∆EXON2") lacking an N-terminal 20AA domain. Based on the substantial penetrance of the urticaria phenotype associated with this variant, an initial working hypothesis is framed as: full-length C1ORF150 normally functions to suppress mast cell activation / degranulation, while isoform C1ORF150-∆EXON2'S N-terminal 20 AA residue deletion corrupts the ability of this adaptor protein (and its partnered effector proteins) to effectively suppress receptor- mediated mast cell activation. This will be tested via the following specific aims. Specific aim #1: we hypothesize that ectopically expressed "C1ORF150- ∆EXON2" will falter in suppressing ligand- induced mast cell degranulation due to its compromised ability to act with CO-effector proteins at the level of FCER1, MRGPRX2 and/or kit ligation. For full-length C1ORF150, its ectopic expression is predicted to reinforce its suppression of mast cell activation. C1ORF150-∆EXON2, and C1ORF150, will be ectopically expressed in LAD2 cells and human IPS cell-derived mast cells. Effects on spontaneous, and IGE/AER-, SP-, and/or SCF- induced activation will then be assessed. Specific aim #2 will employ a loss-of-function approach towards initially defining effects normally exerted by endogenous full-length C1ORF150 on spontaneous, and/or ligand-induced mast cell activation / degranulation. A prime prediction is that C1ORF150'S knockdown will heighten mast cell activation, but in ways that are distinct from the signal- corrupting effects hypothesized to be exerted by its variant C1ORF150-∆EXON2 form. Aim #2 will employ a shrna knockdown approach to inform on effects normally exerted by endogenous full-length C1ORF150 on human mast cell activation / degranulation. This will include analyses in LAD2 and IPS cell-derived mast cells. Investigations promise to provide the first insight into: (1) effects of [RS56043070(a)] and its encoded C1ORF150-∆EXON2 isoform (VS full-length C1ORF150) on mast cell activation; and (2) specific roles played by endogenous C1ORF150 during spontaneous and/or ligand- induced mast cell activation. These findings will begin to illuminate how genetic variance in C1ORF150 influences mast cell hyper-sensitivity in chronic urticaria, and may open avenues for small molecule and genotype- directed treatment approaches.