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A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy.
J Clin Immunol ; 33(6): 1088-99, 2013 Aug.
Article en En | MEDLINE | ID: mdl-23708964
PURPOSE: This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. METHODS: NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. RESULTS: Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. CONCLUSION: The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Displasia Ectodérmica / Núcleo Celular / Poliendocrinopatías Autoinmunes / Quinasa I-kappa B / Fibroblastos / Síndromes de Inmunodeficiencia Tipo de estudio: Prognostic_studies Idioma: En Revista: J Clin Immunol Año: 2013 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Displasia Ectodérmica / Núcleo Celular / Poliendocrinopatías Autoinmunes / Quinasa I-kappa B / Fibroblastos / Síndromes de Inmunodeficiencia Tipo de estudio: Prognostic_studies Idioma: En Revista: J Clin Immunol Año: 2013 Tipo del documento: Article