Abstract
Patients with hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations have extensive phenotypic variability that can include atypical infectious susceptibility. This study may provide important insight into immunologic mechanisms of host defense. Immunologic evaluation, including studies of Toll-like receptor (TLR) function, was performed in a 6-month-old boy with normal ectodermal development who was diagnosed with Pneumocystis pneumonia and cytomegalovirus sepsis. Genomic and cDNA sequencing demonstrated a novel NEMO missense mutation, 337G->A, predicted to cause a D113N (aspartic acid to asparagine) substitution in the first coiled-coil region of the NEMO protein. Quantitative serum immunoglobulins, lymphocyte subset numbers, and mitogen-induced lymphocyte proliferation were essentially normal. The PBMC responses to TLR ligands were also surprisingly normal, whereas natural killer cell cytolytic activity, T-cell proliferative responses to specific antigens, and T-cell receptor-induced NF-kappaB activation were diminished. Unlike the unique NEMO mutation described here, the most commonly reported mutations are clustered at the 3' end in the tenth exon, which encodes a zinc finger domain. Because specific hypomo...Continue Reading
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