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Family Study Uncovers Mutation Involved in Rare Vibration Allergy

NEW YORK (GenomeWeb) – A study appearing online last night in the New England Journal of Medicine suggests that a rare, inherited allergy to vibrations called vibratory urticaria can result from a mutation in an adhesion G-protein coupled receptor subfamily gene ADGRE2.

Researchers from the National Institute of Allergy and Infectious Diseases and elsewhere used a combination of linkage mapping, exome sequencing, and/or targeted sequencing to sequence samples from three multi-generation Lebanese families affected by vibratory urticaria, a condition characterized by localized welts, other allergic reactions, and inflammatory immune response to relatively minor skin vibrations from clothing, towels, or other sources.

The search led to a missense glitch in ADGRE2 that belonged to a broader haplotype present in affected individuals from two of the vibratory urticaria-affected families, the team noted. And the group's subsequent analyses suggest the shared vibratory urticaria-related mutation alters the interactions by the ADGRE2 gene product, making histamine-releasing mast immune cells more sensitive-than-usual to vibration.

These and other findings from the study suggest that "a normal response to vibration, which does not cause symptoms in most people, is exaggerated in our patients with this inherited form of vibratory urticaria," the study's senior author Hirsh Komarow, with the NIAID allergic diseases laboratory, said in a statement.

After charting histamine levels in individuals with vibratory urticaria who were exposed to a round of forearm vortexing, Komarow and his colleagues used linkage analyses on two large, affected Lebanese families to narrow in on a suspicious chromosome 19 region.

With exome sequencing on three affected members of one of the families, they then uncovered three candidate mutations that got whittled down to the missense change in ADGRE2 mutation through Sanger sequencing validation and testing on affected members of the second family.

The missense ADGRE2 mutation did not turn up in the team's search of available variant databases or samples from more than 1,200 unaffected individuals from Lebanon or Israel. On the other hand, a heterozygous version of the ADGRE2 glitch was present in an affected individual from a third family that was prone to vibratory urticaria.

Following a series of follow-up experiments, which included a look at mast cell activity in vibration-exposed primary mast cell samples from two vibratory uriticaria-affected individuals, the researchers concluded that the newly detected ADGRE2 mutation likely leads to less stable interactions between the subunit the gene encodes, prompting over-the-top inflammatory responses mediated by mast cells.

The study's authors noted that "[t]he physiological role of ADGRE2 in mast cells and other myeloid cell types remains to be determined, though they cited past evidence supporting the hypothesis that it plays a role in at least innate immune responses. 

"The aberrant degranulation associated with vibratory urticaria suggests that dermal mast cells may respond to physical forces through ADGRE2," they wrote, "in addition to their known response to allergic stimuli."