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.
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-kappaBhaploinsufficiency 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.
Authors: Manfred Fliegauf; Vanessa L Bryant; Natalie Frede; Charlotte Slade; See-Tarn Woon; Klaus Lehnert; Sandra Winzer; Alla Bulashevska; Thomas Scerri; Euphemia Leung; Anthony Jordan; Baerbel Keller; Esther de Vries; Hongzhi Cao; Fang Yang; Alejandro A Schäffer; Klaus Warnatz; Peter Browett; Jo Douglass; Rohan V Ameratunga; Jos W M van der Meer; Bodo Grimbacher Journal: Am J Hum Genet Date: 2015-08-13 Impact factor: 11.025
Authors: Gabriele Neu-Yilik; Beate Amthor; Niels H Gehring; Sharif Bahri; Helena Paidassi; Matthias W Hentze; Andreas E Kulozik Journal: RNA Date: 2011-03-09 Impact factor: 4.942
Authors: Enrica Ek Tan; Richard A Hopkins; Chrissie K Lim; Saumya S Jamuar; Christina Ong; Koh C Thoon; Mark Ja Koh; Eun Mong Shin; Derrick Wq Lian; Madhushanee Weerasooriya; Christopher Zw Lee; Andreas Alvin Pumomo Soetedjo; Chang Siang Lim; Veonice B Au; Edmond Chua; Hui Yin Lee; Leigh Ann Jones; Sharmy S James; Nivashini Kaliaperumal; Jeffery Kwok; Ee Shien Tan; Biju Thomas; Lynn Xue Wu; Lena Ho; Anna Marie Fairhurst; Florent Ginhoux; Adrian Kk Teo; Yong Liang Zhang; Kok Huar Ong; Weimiao Yu; Byrappa Venkatesh; Vinay Tergaonkar; Bruno Reversade; Keh Chuang Chin; Ah Moy Tan; Woei Kang Liew; John E Connolly Journal: J Clin Invest Date: 2020-11-02 Impact factor: 14.808
Authors: Lena F Schimke; Nikolaus Rieber; Stacey Rylaarsdam; Otávio Cabral-Marques; Nicholas Hubbard; Anne Puel; Laura Kallmann; Stephanie Anover Sombke; Gundula Notheis; Hans-Peter Schwarz; Birgit Kammer; Tomas Hökfelt; Reinald Repp; Capucine Picard; Jean-Laurent Casanova; Bernd H Belohradsky; Michael H Albert; Hans D Ochs; Ellen D Renner; Troy R Torgerson Journal: J Clin Immunol Date: 2013-05-25 Impact factor: 8.317