Background: Nuclear factor-kappaB (NF-kappaB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IkappaB kinase gamma/NF-kappaB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency.
Objective: To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother.
Methods: TNF-alpha and IFN-alpha production in response to Toll-like receptor (TLR) stimulation was analyzed by ELISA, NEMO mRNA levels were measured by quantitative PCR, and NEMO protein expression was measured by Western blotting. NF-kappaB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays.
Results: TLR-induced TNF-alpha and IFN-alpha production by PBMCs was impaired in the patient and his brother. Sequencing of the patient's NEMO gene revealed a novel mutation in the 5' untranslated region, which was also present in the brother, resulting in abnormally spliced transcripts and a 4-fold reduction in mRNA levels. NEMO protein levels in EBV transformed B cells and fibroblasts from the index patient were 8-fold lower than normal controls. NF-kappaB p65 nuclear translocation in the patient's EBV B cells after TLR7 ligation was defective. NF-kappaB-dependent luciferase gene expression in IL-1-stimulated fibroblasts from the patient was impaired.
Conclusion: This is the first description of immune deficiency resulting from low expression of a normal NEMO protein.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124805 | PMC |
http://dx.doi.org/10.1016/j.jaci.2010.04.026 | DOI Listing |
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