A novel missense mutation in the nuclear factor-κB essential modulator (NEMO) gene resulting In impaired activation of the NF-κB pathway and a unique clinical phenotype presenting as mrsa subdural empyema

Gene A. Devora, Lijun Sun, Zhijian Chen, Nicolai S C Van Oers, Eric P. Hanson, Jordan S. Orange, M. Teresa De La Morena

Research output: Contribution to journalArticle

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Abstract

Introduction:We describe a previously unreported 437 T→G missense mutation producing a V146G substitution in the first coiled-coil (CC1) domain of nuclear factor-κB essential modulator (NEMO) in a 9-month-old boy with ectodermal dysplasia with immunodeficiency who presented with methicillin-resistant Staphylococcus aureus subdural empyema. We performed in vitro experiments to determine if this novel mutation resulted in impaired NF-κB signaling. Methods IκBα phosphorylation experiments were performed using a Jurkat T cell line lacking endogenous NEMO expression that was transfected with vectors containing either the wild type or the patient's V146G mutation. The cells were stimulated with TNF-α to activate the NF-κB pathway. Phosphorylated IκBα was detected by immunoblotting with anti-phospho-IκBα antibodies. Peripheral blood mononuclear cells from the patient were stimulated with TNF-α or anti-CD3 and anti-CD28. Impaired IκBα degradation was detected using antibodies against the IκBα protein. Results While TNF-α stimulation resulted in IκBα phosphorylation in NEMO-deficient Jurkat cells reconstituted with wild-type NEMO, cell transfected with the V146G mutant exhibited a 75% reduction in phospho-IκBα. Peripheral blood mononuclear cells from the patient showed impaired degradation of IκBα after stimulation when compared with normal controls. Conclusions The patient's V146G mutation results in impaired NF-κB activation in vitro. The mutation extends the known N-terminal boundary within the CC1 domain that produces an ectodermal dysplasia phenotype, and defines an infectious susceptibility previously unappreciated in ectodermal dysplasia with immunodeficiency (methicillin-resistant S. aureus subdural empyema), broadening the clinical spectrum associated with the disease.

Original languageEnglish (US)
Pages (from-to)881-885
Number of pages5
JournalJournal of Clinical Immunology
Volume30
Issue number6
DOIs
StatePublished - Nov 1 2010

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Keywords

  • Ectodermal dysplasia
  • Immunodeficiency
  • MRSA
  • Mutation
  • NEMO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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