Vibratory Urticaria Associated with a Missense Variant inADGRE2

Abstract

SUMMARY Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.)

Activation of Adhesion GPCR EMR2/ADGRE2 Induces Macrophage Differentiation and Inflammatory Responses via Gα16/Akt/MAPK/NF-κB Signaling Pathways

“…The identification of EMR2/ADGRE2 as the vibratory urticaria-inducing molecule attests to the functional importance of this myeloid-restricted aGPCR (19). While accumulating evidence is emerging for a signaling role of EMR2 in myeloid cells, the actual pathways and significance of EMR2-mediated signaling are not understood.…”

“…More recently, a missense EMR2-C492Y variant was identified as the disease protein responsible for the autosomal dominant vibratory urticaria, a dermal vibration-induced hives. It was shown that the disease-associated EMR2 variant was less stable and prone to sensitize mast cells for aberrant histamine release upon vibratory stimulation in the presence of dermatan sulfate or 2A1 (19). …”

Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease

“…The ECD displacement unmasks the amino-terminal stalk regions of 7TM, which serve as autoligands essential for G protein signaling (Stoveken et al 2015). A missense variant ( p.C492Y) in the GAIN domain of another aGPCR, ADGRE2 (EMR2), weakens the ECD and 7TM autoinhibitory interaction and sensitizes mast cells to vibration-induced degranulation in a familial form vibratory urticaria (Boyden et al 2016).…”

Increased EMR2 expression on neutrophils correlates with disease severity and predicts overall mortality in cirrhotic patients

“…Furthermore, other studies had shown that EMR2 expression on the neutrophil increased in patients with SIRS and correlated with the extent of organ failure12. Its gene variant could sensitize mast cells to IgE-independent vibration-induced degranulation13. On the contrary, evidences for EMR2 expression on neutrophils associated with sepsis14 and ligation of EMR2 could suppresses LPS-induced neutrophil survival had been revealed15.…”