Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of the NEMO gene - 07/08/11
, Douglas R. McDonald, MD, PhD a, ⁎ Reprint requests: Raif S. Geha, MD, or Douglas R. McDonald, MD, PhD, Division of Immunology, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115.Abstract |
Background |
Nuclear factor-κB (NF-κB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IκB kinase γ/NF-κB 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-⍺ and IFN-⍺ 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-κB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays.
Results |
TLR-induced TNF-⍺ and IFN-⍺ 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-κB p65 nuclear translocation in the patient’s EBV B cells after TLR7 ligation was defective. NF-κB–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.
Le texte complet de cet article est disponible en PDF.Key words : NEMO, immune deficiency, recurrent infections, 5′ untranslated region mutation
Abbreviations used : EDID, IκB, IKK, NEMO, NF-κB, TLR, UTR
Plan
| Supported by National Institutes of Health grants AI076210 (to R.S.G.) and AI076625 (to D.R.M.). J.L.M. is supported by the Stern Family Fund at Children’s Hospital Boston. |
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| Disclosure of potential conflict of interest: R. S. Geha has received research support from the National Institutes of Health and the March of Dimes. The rest of the authors have declared that they have no conflict of interest. |
Vol 126 - N° 1
P. 127 - juillet 2010 Retour au numéro
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