THE ASSOCIATION OF ATOPY WITH A GAIN-OF-FUNCTION MUTATION IN THE ALPHA-SUBUNIT OF THE INTERLEUKIN-4 RECEPTOR

Background Atopic diseases are very common, and atopy has a strong gen etic predisposition. Methods Using single-strand conformation polymorp hism analysis and DNA sequencing, we searched for mutations in the alp ha subunit of the interleukin-4 receptor that would predispose persons to atopy. We examined the prevalence of the alleles among patients wi th allergic inflammatory disorders and among 50 prospectively recruite d adults. Subjects with atopy were identified on the basis of an eleva ted serum IgE level (greater than or equal to 95 IU per milliliter) or a positive radioimmunosorbent test in response to standard inhalant a llergens. The signaling function of mutant interleukin-4 receptor alph a was examined by flow cytometry, binding assays, and immunoblotting. Results A novel interleukin-4 receptor alpha allele was identified in which guanine was substituted for adenine at nucleotide 1902, causing a change from glutamine to arginine at position 576 (R576) in the cyto plasmic domain of the interleukin-4 receptor alpha protein. The R576 a llele was common among patients with allergic inflammatory disorders ( found in 3 of 3 patients with the hyper-IgE syndrome and 4 of 7 patien ts with severe atopic dermatitis) and among the 50 prospectively recru ited adults (found in 13 of 20 subjects with atopy and 5 of 30 without atopy; P=0.001; relative risk of atopy among those with a mutant alle le, 9.3). The R576 allele was associated with higher levels of express ion of CD23 by interleukin-4 than the wild-type allele. This enhanced signaling was associated with a change in the binding specificity of t he adjacent tyrosine residue at position 575 to signal-transducing mol ecules. Conclusions The R576 allele of interleukin-4 receptor alpha is strongly associated with atopy. This mutation may predispose persons to allergic diseases by altering the signaling function of the recepto r. (C) 1997, Massachusetts Medical Society.