Background: Nuclear factor kappaB (NF-kappaB) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the IkappaB kinase gamma/NF-kappaB essential modifier have been described in male subjects with the syndrome of X-linked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-kappaB.
Objectives: We sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient.
Methods: Toll-like receptor-induced production of the NF-kappaB-dependent cytokines TNF-alpha and IFN-alpha was examined by means of ELISA, the patient's IkappaBalpha gene was sequenced, and NF-kappaB activation was evaluated by means of electrophoretic mobility shift assay and NF-kappaB-luciferase assays in transfectants.
Results: Toll-like receptor function was impaired in the patient. Sequencing of the patient's IkappaBalpha gene revealed a novel heterozygous mutation at amino acid 11 (W11X). The mutant IkappaBalphaW11X protein did not undergo ligand-induced phosphorylation or degradation and retained NF-kappaB in the cytoplasm. This led to roughly a 50% decrease in NF-kappaB DNA-binding activity, leading to functional haploinsufficiency of NF-kappaB activation. Unlike the only other reported IkappaBalpha mutant associated with ectodermal dysplasia associated with immune deficiency (ED-ID), S32I, IkappaBalphaW11X exerted no dominant-negative effect.
Conclusions: Functional NF-kappaB haploinsufficiency was associated with ED-ID, and this strongly suggests that normal ectodermal development and immune function are stringently dependent on NF-kappaB in that they might require more than half of normal NF-kappaB activity.
Clinical Implications: Although ED-ID is well described in male subjects, female subjects can present with a similar syndrome of ectodermal dysplasia with immune deficiency resulting from mutations in autosomal genes within the NF-kappaB pathway.
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http://dx.doi.org/10.1016/j.jaci.2007.08.035 | DOI Listing |
Pediatr Int
December 2024
Center for Perinatal and Neonatal Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan.
Background: Clinical studies have shown that diffuse chorioamniotic hemosiderosis (DCH) is a risk factor for bronchopulmonary dysplasia (BPD). However, the details of the underlying mechanism are unknown. We focused on iron, one of the blood components that diffuses within the amniotic cavity in DCH.
View Article and Find Full Text PDFPediatr Dermatol
December 2024
Department of Pediatric Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
We describe a 1-day old female with features of keratitis-ichthyosis-deafness (KID) syndrome and natal teeth. Genetic analysis confirmed GJB2 263C and A88V de novo pathogenic variants consistent with KID syndrome. Natal teeth were promptly extracted to avoid the risk of aspiration.
View Article and Find Full Text PDFClin Oral Investig
December 2024
Postgraduate in Oral Surgery, University of Florence, Florence, Italy.
Background: Tooth agenesis refers to the absence of one or more of the deciduous or permanent teeth. Tooth agenesis results from a series of disrupted reciprocal ectodermal mesenchymal interactions taking place during the early stages of tooth development.
Methods: A narrative literature review was performed to describe the main genetic syndromes associated with tooth agenesis.
Cell Commun Signal
December 2024
CNR Institute of Biochemistry and Cell Biology, Monterotondo, Rome, 00015, Italy.
Connexins (Cxs) are fundamental in cell-cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca signaling, which is crucial for proper PNS myelination.
View Article and Find Full Text PDFAnticancer Res
December 2024
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
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