A Novel Missense Mutation in the Nuclear Factor-kappa B Essential Modulator (NEMO) Gene Resulting in Impaired Activation of the NF-kappa B Pathway and a Unique Clinical Phenotype Presenting as MRSA Subdural Empyema

作者：Devora Gene A; Sun Lijun; Chen Zhijian; van Oers Nicolai S C; Hanson Eric P; Orange Jordan S; de la Morena M Teresa^*

来源：Journal of Clinical Immunology, 2010, 30(6): 881-885.

DOI：10.1007/s10875-010-9445-y

• NEMO
• immunodeficiency
• ectodermal dysplasia
• mutation
• MRSA

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-kappa B 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-kappa B signaling.
Methods I kappa B alpha 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 TNT-alpha to activate the NF-kappa B pathway. Phosphorylated I kappa B alpha was detected by immunoblotting with anti-phospho-I kappa B alpha antibodies. Peripheral blood mononuclear cells from the patient were stimulated with TNF-alpha or anti-CD3 and anti-CD28. Impaired IKBa degradation was detected using antibodies against the I kappa B alpha protein.
Results While TNF-a stimulation resulted in I kappa B alpha phosphorylation in NEMO-deficient Jurkat cells reconstituted with wild-type NEMO, cell transfected with the V146G mutant exhibited a 75% reduction in phospho-I kappa B alpha. Peripheral blood mononuclear cells from the patient showed impaired degradation of I kappa B alpha after stimulation when compared with normal controls.
Conclusions The patient's V146G mutation results in impaired NF-kappa B activation in vitro. The mutation extends the known N-terminal boundary within the CC1 domain that produces an ectodennal 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.

• 出版日期2010-11