Correspondence

The Interleukin-4 Receptor Variant Q576R in Hyper-IgE Syndrome

N Engl J Med 1998; 338:1073-1074April 9, 1998

Article

To the Editor:

The hyper-IgE recurrent-infection syndrome (Online Mendelian Inheritance in Man no. 243700), also called Job's syndrome, is a rare immunodeficiency disorder that is characterized by recurrent staphylococcal skin abscesses, pneumonia, and elevated serum IgE concentrations (>2000 IU per milliliter).1,2 The known involvement of the interleukin-4 pathway in atopy and IgE isotype switching3 led Hershey et al. (Dec. 11 issue)4 to search for mutations in the α subunit of the interleukin-4 receptor. All three of their patients with the hyper-IgE syndrome were heterozygous for an interleukin-4 receptor variant allele (Q576R). The Q576R mutation was also found in 10 percent of the interleukin-4 receptor alleles in normal subjects, but it was significantly more common among patients with severe atopic disease.

We investigated the frequency of Q576R in 25 control subjects and 20 unrelated patients with the hyper-IgE syndrome who were followed in collaboration with Drs. John Gallin and Harry Malech at the National Institutes of Health Clinical Center. Q576R was detected in DNA samples by single-strand conformation polymorphism analysis (Figure 1Figure 1Single-Strand Conformation Polymorphism Analysis of the Interleukin-4 Receptor Gene in 20 Unrelated Patients with the Hyper-IgE Syndrome and Three Relatives of Subject 20.) and confirmed by sequence analysis (data not shown). Only 4 of 20 patients with the hyper-IgE syndrome had the Q576R mutation (allelic frequency, 10 percent), which was not significantly different from the frequency of 12 percent in the control subjects (6 of 25). In the case of nine of the patients, family members were also studied. In five families Q576R was not detected, and in three families an unaffected parent was heterozygous for the mutation but did not transmit this variant allele to the affected child. In one family (Figure 1), the healthy, nonatopic mother (Subject I-1) was homozygous for Q576R and her three children were heterozygous for the mutation, but only one child (Subject 20) had the hyper-IgE syndrome.

All the patients in our cohort had elevated serum IgE concentrations (Figure 1). If Q576R predisposes persons to atopy, as suggested by Hershey et al., one might expect patients with the hyper-IgE syndrome and the Q576R mutation to have higher IgE concentrations. However, it is clear from Figure 1 that this was not the case.

It is possible that other mutations in the interleukin-4 receptor gene or mutations in a nearby gene could be causally associated with the hyper-IgE syndrome. To evaluate whether the syndrome is genetically linked to the interleukin-4 receptor gene on chromosome 16, seven families with autosomal dominant hyper-IgE syndrome were genotyped with polymorphic markers surrounding the interleukin-4 receptor locus. After conducting multiple analyses using programs from the Fastlink package,5 we concluded that the interleukin-4 receptor gene is not linked to the hyper-IgE syndrome. For example, four-point Linkmap analysis with the ordered markers D16S769, D16S753, and ATA55A11 (the outer two are known to flank the interleukin-4 receptor gene) gave a maximal lod score of less than -2.5 for the location of the hyper-IgE syndrome between the first two markers, and of less than -5.0 for its location between the second two markers.

Our data agree with those of Hershey et al. in suggesting that the Q576R variant occurs in about 10 percent of interleukin-4 receptor gene alleles in healthy persons. However, our analysis of a large cohort of patients with the hyper-IgE syndrome not only showed no increase in the frequency of Q576R as compared with that in normal subjects, but also ruled out the possibility of genetic linkage between the syndrome and the interleukin-4 receptor locus.

Bodo Grimbacher, M.D.
National Human Genome Research Institute

Steven M. Holland, M.D.
National Institute for Allergy and Infectious Diseases

Jennifer M. Puck, M.D.
National Human Genome Research Institute, Bethesda, MD 20892

5 References

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Author/Editor Response

The authors reply:

To the Editor: Grimbacher and colleagues analyzed the frequency of the interleukin-4 receptor R576 allele in 20 patients with the hyper-IgE syndrome and found no increase in the frequency of this allele in patients relative to that in healthy control subjects. Our identification of nonatopic subjects who are heterozygous and even homozygous for the R576 allele effectively ruled it out as a cause of hyper-IgE syndrome, although its presence in all three patients with the syndrome whom we examined suggested a contribution of this allele to the pathogenesis of the syndrome. The data of Grimbacher et al. suggest otherwise, and it remains to be determined whether the presence of the R576 allele in all three of our patients was a chance occurrence or reflective of differences in the patients' characteristics (e.g., our patients had sporadic cases of disease rather than familial forms).

The failure of Grimbacher et al. to find a correlation between IgE levels in their patients and the presence of the R576 allele is not surprising. IgE levels are extremely elevated in this syndrome, presumably because of a distinct primary genetic defect, which may obscure a contribution by atopy-susceptibility alleles. The association of IL-4R alleles with atopy has been established by another recent study.1 The contribution of these alleles to atopic diseases remains the subject of ongoing studies.

Gurjit K. Khurana Hershey, M.D.
Children's Hospital Medical Center, Cincinnati, OH 45229

Talal A. Chatila, M.D.
Washington University School of Medicine, St. Louis, MO 63110

1 References

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   Deichmann KA, Heinzmann A, Forster J, et al. Linkage and allelic association of atopy and markers flanking the IL4-receptor gene. Clin Exp Allergy 1998;28:151-155
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   K. O. GUDMUNDSSON, O. E. SIGURJONSSON, S. GUDMUNDSSON, D. GOLDBLATT, C. M. R. WEEMAES, A. HARALDSSON. (2002) Increased expression of interleukin-13 but not interleukin-4 in CD4 ⁺ cells from patients with the hyper-IgE syndrome. Clinical & Experimental Immunology 128:3, 532-537
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    Ec Tan, Bw Lee, Awn Tay, L Shek, Ft Chew, Ahn Tay. (1999) Interleukin-4 receptor variant Q576R: ethnic differences and association with atopy. Clinical Genetics 56:4, 333-334
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    B GRIMBACHER, A SCHAFFER, S HOLLAND, J DAVIS, J GALLIN, H MALECH, T ATKINSON, B BELOHRADSKY, R BUCKLEY, F COSSU. (1999) Genetic Linkage of Hyper-IgE Syndrome to Chromosome 4. The American Journal of Human Genetics 65:3, 735-744
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