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
| Autor: | Alessandra Simonetti, Luigi D. Notarangelo, Jana L. Mooster, Caterina Cancrini, Maria Luisa Romiti, Raif S. Geha, Gigliola Di Matteo, Paolo Rossi, Silvia Di Cesare, Douglas R. McDonald |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Untranslated region congenital hereditary and neonatal diseases and abnormalities Five prime untranslated region Interleukin-1beta Immunology Biology medicine.disease_cause Article chemistry.chemical_compound NF-KappaB Inhibitor alpha IKBKG medicine Humans Immunology and Allergy Coding region RNA Messenger Phosphorylation Child Gene Settore MED/38 - Pediatria Generale e Specialistica Mutation Toll-Like Receptors Immunologic Deficiency Syndromes NF-kappa B NF-κB NFKB1 Molecular biology I-kappa B Kinase chemistry Cytokines I-kappa B Proteins RNA Splice Sites 5' Untranslated Regions |
| Zdroj: | Journal of Allergy and Clinical Immunology. 126:127-132.e7 |
| ISSN: | 0091-6749 |
| Popis: | 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-α and IFN-α 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-α and IFN-α 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. |
| Databáze: | OpenAIRE |
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