A novel truncating mutation in MYD88 in a patient with BCG adenitis, neutropenia and delayed umbilical cord separation

Abstract

Mutations in MYD88 cause susceptibility to invasive bacterial infections through impaired signaling downstream of toll-like receptors (TLRs) and IL-1 receptors. We studied a patient presenting with neutropenia, delayed umbilical cord separation, BCG adenitis, andP. aeruginosapneumonia. Next-generation DNA sequencing identified a novel homozygous truncation mutation in MYD88 that abolishes MyD88 expression. The patient's dermal fibroblasts had severely impaired IL-6 production after stimulation with ligands for the MyD88-dependent receptors TLR2, TLR4 and IL-1R, while responses to ligands for the MyD88-independent receptors TLR3 and TNF-α were preserved. Notably, secretion of TNF-α, which is essential for BCG control, was also impaired after LPS stimulation. In this first report of BCG infection in MyD88 deficiency, data suggest that MyD88-dependent TNF-α production contributes to control of mycobacterial disease.

Keywords: BCG; Delayed umbilical cord separation; MyD88 deficiency; Neutropenia.

Figure 1.

A. Family pedigree. B. Sanger sequencing of the c.814C>T variant. C. MyD88 protein domains. Red arrow indicates position of the patient’s mutation, black arrows indicate previously reported mutations. DD, Death domain; TIR, TIR domain. D. Immunoblot of dermal fibroblast lysates derived from patients and controls. Representative of 2 independent experiments. E, F. Toll-like receptor (TLR) signaling in patient fibroblasts. Dermal fibroblasts from patient and two healthy controls were stimulated as indicated and IL-6 (E) or TNF-α (F) production was assessed by ELISA. Pooled from 2 independent experiments. Columns and bars represent means and SEM. * p<0.05, **p<0.01; Student’s t test.