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. 2009 Oct 29;361(18):1760-7.
doi: 10.1056/NEJMoa0901053.

Human dectin-1 deficiency and mucocutaneous fungal infections

Bart Ferwerda  1 , Gerben Ferwerda, Theo S Plantinga, Janet A Willment, Annemiek B van Spriel, Hanka Venselaar, Clara C Elbers, Melissa D Johnson, Alessandra Cambi, Cristal Huysamen, Liesbeth Jacobs, Trees Jansen, Karlijn Verheijen, Laury Masthoff, Servaas A Morré, Gert Vriend, David L Williams, John R Perfect, Leo A B Joosten, Cisca Wijmenga, Jos W M van der Meer, Gosse J Adema, Bart Jan Kullberg, Gordon D Brown, Mihai G Netea
Affiliations

Human dectin-1 deficiency and mucocutaneous fungal infections

Bart Ferwerda et al. N Engl J Med. .

Abstract

Mucocutaneous fungal infections are typically found in patients who have no known immune defects. We describe a family in which four women who were affected by either recurrent vulvovaginal candidiasis or onychomycosis had the early-stop-codon mutation Tyr238X in the beta-glucan receptor dectin-1. The mutated form of dectin-1 was poorly expressed, did not mediate beta-glucan binding, and led to defective production of cytokines (interleukin-17, tumor necrosis factor, and interleukin-6) after stimulation with beta-glucan or Candida albicans. In contrast, fungal phagocytosis and fungal killing were normal in the patients, explaining why dectin-1 deficiency was not associated with invasive fungal infections and highlighting the specific role of dectin-1 in human mucosal antifungal defense.

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Figures

Figure 1
Figure 1. Dectin-1 Mutation in a Family with Mucocutaneous Fungal Infections
Panel A shows the structure of the dectin-1 gene and the location of an early-stop-codon mutation consisting of a homozygous single-nucleotide polymorphism (rs16910526, exon 6, chromosome 12; location, 10162354 bp). The mutation (A→C) causes a change of amino acid 238 from tyrosine to a stop codon (Tyr238X), leading to the loss of the last nine amino acids of the carbohydrate-recognition domain (CRD). Cyto denotes the cytoplasmic tail and TM the transmembrane region. Panel B shows the genetic pedigree of the index family with dectin-1 deficiency. Circles indicate female patients; the square indicates the father. Solid symbols denote homozygosity for the mutation (X/X, seen in all three daughters), and half-solid symbols denote heterozygosity (X/Tyr, seen in the parents).
Figure 2
Figure 2. Functional Defects Resulting from Dectin-1 Mutation
Panel A shows interleukin-6 production in monocytes isolated after stimulation for 4 hours with β-glucan — for five healthy subjects with wild-type dectin-1 (with data pooled), the two patients who were heterozygous for the dectin-1 mutation, and the three patients who were homozygous for the mutation. Panel B shows the mean binding of nonopsonized fluorescent heat-killed Candida albicans to monocytes isolated from healthy subjects with wild-type dectin-1 and from the patients who were homozygous for the mutation. In both panels, T bars indicate standard deviations.
Figure 3
Figure 3. Polymorphisms and Haplotypes of the Dectin-1 Stop Mutation Worldwide
The frequency of the dectin-1 polymorphism rs16910526 is shown for various populations of the world. The ancestral allele A leads to a functional dectin-1 receptor, whereas the derived allele C leads to an early-stop-codon mutation and nonfunctional dectin-1 receptor. The derived allele is observed only in populations from Africa and western Eurasia. The highest prevalence of the mutation (nearly 40%) is found in the San population in South Africa.
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