The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes.
Identifieur interne : 000649 ( France/Analysis ); précédent : 000648; suivant : 000650The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes.
Auteurs : Asma Smahi [France] ; Gilles Courtois ; Smail Hadj Rabia ; Rainer Döffinger ; Christine Bodemer ; Arnold Munnich ; Jean-Laurent Casanova ; Alain IsraëlSource :
- Human molecular genetics [ 0964-6906 ] ; 2002.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : NF-kappa B.
- metabolism : Ectodermal Dysplasia, Immunologic Deficiency Syndromes, Incontinentia Pigmenti.
- Animals, Disease Models, Animal, Humans, Signal Transduction.
Abstract
The transcription factor NF-kappaB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-kappaB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-kappaB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-kappaB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). The immunological and infectious features observed in patients result from impaired NF-kappaB signalling, including cellular response to LPS, IL-1beta, IL-18, TNF-alpha, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-kappaB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-kappaB signalling pathway.
PubMed: 12351572
Affiliations:
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pubmed:12351572Le document en format XML
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type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Courtois, Gilles" sort="Courtois, Gilles" uniqKey="Courtois G" first="Gilles" last="Courtois">Gilles Courtois</name></author><author><name sortKey="Rabia, Smail Hadj" sort="Rabia, Smail Hadj" uniqKey="Rabia S" first="Smail Hadj" last="Rabia">Smail Hadj Rabia</name></author><author><name sortKey="Doffinger, Rainer" sort="Doffinger, Rainer" uniqKey="Doffinger R" first="Rainer" last="Döffinger">Rainer Döffinger</name></author><author><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name></author><author><name 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(métabolisme)</term><term>Modèles animaux de maladie humaine</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>NF-kappa B</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Ectodermal Dysplasia</term><term>Immunologic Deficiency Syndromes</term><term>Incontinentia Pigmenti</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Dysplasie ectodermique</term><term>Déficits immunitaires</term><term>Facteur de transcription NF-kappa B</term><term>Incontinentia pigmenti</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Humans</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Modèles animaux de maladie humaine</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The transcription factor NF-kappaB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-kappaB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-kappaB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-kappaB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). The immunological and infectious features observed in patients result from impaired NF-kappaB signalling, including cellular response to LPS, IL-1beta, IL-18, TNF-alpha, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-kappaB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-kappaB signalling pathway.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><noCountry><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><name sortKey="Courtois, Gilles" sort="Courtois, Gilles" uniqKey="Courtois G" first="Gilles" last="Courtois">Gilles Courtois</name><name sortKey="Doffinger, Rainer" sort="Doffinger, Rainer" uniqKey="Doffinger R" first="Rainer" last="Döffinger">Rainer Döffinger</name><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israël">Alain Israël</name><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><name sortKey="Rabia, Smail Hadj" sort="Rabia, Smail Hadj" uniqKey="Rabia S" first="Smail Hadj" last="Rabia">Smail Hadj Rabia</name></noCountry><country name="France"><region name="Île-de-France"><name sortKey="Smahi, Asma" sort="Smahi, Asma" uniqKey="Smahi A" first="Asma" last="Smahi">Asma Smahi</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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