title: Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.
abstract: NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IκBα, affecting NF-κB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females.
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico.
authors.forename: Noé
authors.initials: N
authors.lastname: Ramírez-Alejo
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Alcántara-Montiel
authors.affiliation: Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City 04530, Mexico.
authors.forename: Marco
authors.initials: M
authors.lastname: Yamazaki-Nakashimada
authors.affiliation: Department of Dermatology, National Institute of Pediatrics, Mexico City 04530, Mexico.
authors.forename: Carola
authors.initials: C
authors.lastname: Duran-McKinster
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico.
authors.forename: Paola
authors.initials: P
authors.lastname: Valenzuela-León
authors.affiliation: Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City 04530, Mexico.
authors.forename: Francisco
authors.initials: F
authors.lastname: Rivas-Larrauri
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico.
authors.forename: Leticia
authors.initials: L
authors.lastname: Cedillo-Barrón
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Hernández-Rivas
authors.affiliation: Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City 07360, Mexico. Electronic address: lesantos@cinvestav.mx.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Santos-Argumedo
mesh_terms: D000293:Adolescent; D000328:Adult; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000276:immunology; D005190:Family; D005260:Female; D006579:Heterozygote; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D007184:Incontinentia Pigmenti / Q000235:genetics* / Q000276:immunology; D008297:Male; D020125:Mutation, Missense; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics* / Q000276:immunology; D054875:Ubiquitination / Q000235:genetics* / Q000276:immunology
chemical_list: C491731:IKBKG protein, human; D051550:I-kappa B Kinase
keywords: Ectodermal dysplasia; Immune thrombocytopenic purpura; Immunodeficiency; NEMO