Journal ArticleDOI
Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.
A. Smahi,Gilles Courtois,Pierre Vabres,Shoji Yamaoka,S. Heuertz,Arnold Munnich,Alain Israël,Nina S. Heiss,Sabine M. Klauck,Petra Kioschis,Stefan Wiemann,Annemarie Poustka,Teresa Esposito,T. Bardaro,Fernando Gianfrancesco,Alfredo Ciccodicola,Michele D'Urso,Hayley Woffendin,T. Jakins,D. Donnai,H. Stewart,Susan Kenwrick,Swaroop Aradhya,Takanori Yamagata,Michael J. Levy,Richard A. Lewis,David L. Nelson +26 more
TLDR
Most cases of familial incontinentia pigmenti are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations, which means that NF-κB activation is defective in IP cells.Abstract:
Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.read more
Citations
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Journal ArticleDOI
NF-κB Essential Modulator (NEMO) Interaction with Linear and Lys-63 Ubiquitin Chains Contributes to NF-κB Activation
Kamyar Hadian,Richard A. Griesbach,Scarlett Dornauer,Tim M. Wanger,Daniel Nagel,Moritz Metlitzky,Wolfgang Beisker,Marc Schmidt-Supprian,Daniel Krappmann +8 more
TL;DR: In vivo NEMO interaction with linear and Lys-63 ubiquitin chains is required for optimal IKK activation, suggesting that both type of chains are cooperating in triggering canonical NF-κB signaling.
Journal ArticleDOI
TAB2, TRAF6 and TAK1 are involved in NF-κB activation induced by the TNF-receptor, Edar and its adaptator Edaradd
TL;DR: Results support the involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway and have important implications for the understanding of NF-kappaB activation and EDs in human.
Journal ArticleDOI
Human disease resulting from gene mutations that interfere with appropriate nuclear factor‐κB activation
TL;DR: An increasing number of human genetic lesions that result in defined disease entities are linked to inappropriate activation of NF‐κB, which can lead to cellular defects that ultimately impair normal developmental processes, host immune defenses, or both.
Journal ArticleDOI
ISG15: leading a double life as a secreted molecule
Dusan Bogunovic,Stéphanie Boisson-Dupuis,Stéphanie Boisson-Dupuis,Jean-Laurent Casanova,Jean-Laurent Casanova +4 more
TL;DR: The studies described here pave the way for clinical studies of various aspects, ranging from the use of recombinant ISG15 in patients with infectious diseases to theUse of ISG 15-blocking agents in patientsWith inflammatory diseases, as well as raising mechanistic issues.
Journal ArticleDOI
The X-files of inflammation: Cellular mosaicism of X-linked polymorphic genes and the female advantage in the host response to injury and infection
TL;DR: It is argued that the sex benefit of females during the host response is associated with polymorphism of X- linked genes and cellular mosaicism for X-linked parental alleles, which represents a more adaptive and balanced cellular machinery that is advantageous during the innate immune response.
References
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NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses
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Suppression of TNF-α-Induced Apoptosis by NF-κB
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Journal ArticleDOI
Complementation Cloning of NEMO, a Component of the IκB Kinase Complex Essential for NF-κB Activation
Shoji Yamaoka,Gilles Courtois,Christine Bessia,Simon T. Whiteside,Robert Weil,Fabrice Agou,Heather Kirk,Robert J. Kay,Alain Israël +8 more
TL;DR: A flat cellular variant of HTLV-1 Tax-transformed rat fibroblasts, 5R, which is unresponsive to all tested NF-κB activating stimuli is characterized, and its genetic complementation is reported.
Journal ArticleDOI
Requirement for NF-κB in osteoclast and B-cell development
Guido Franzoso,Louise Carlson,Lianping Xing,Ljiljana Poljak,Elizabeth W. Shores,Keith Brown,Antonio Leonardi,Tom Tran,Brendan F. Boyce,Ulrich Siebenlist +9 more
TL;DR: It is demonstrated that unlike the respective single knockout mice, the p50/p52 double knockout mice fail to generate mature osteoclasts and B cells, apparently because of defects that track with these lineages in adoptive transfer experiments.
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