A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency
Identifieur interne : 000618 ( France/Analysis ); précédent : 000617; suivant : 000619A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency
Auteurs : Gilles Courtois ; Asma Smahi ; Janine Reichenbach [France] ; Rainer Döffinger [France] ; Caterina Cancrini [Italie] ; Marion Bonnet [France] ; Anne Puel [France] ; Christine Chable-Bessia ; Shoji Yamaoka [Japon] ; Jacqueline Feinberg [France] ; Sophie Dupuis-Girod [France] ; Christine Bodemer ; Susanna Livadiotti [Italie] ; Francesco Novelli [France] ; Paolo Rossi [Italie] ; Alain Fischer [France] ; Alain Israël ; Arnold Munnich ; Françoise Le Deist ; Jean-Laurent Casanova [France]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2003.
Abstract
X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKγ, the regulatory subunit of the IκB kinase (IKK) complex. IKK normally phosphorylates the IκB-inhibitors of NF-κB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-κB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IκBα. This mutation is gain-of-function, as it enhances the inhibitory capacity of IκBα by preventing its phosphorylation and degradation, and results in impaired NF-κB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1β, and IL-18), and TNFR (TNF-α, LTα1/β2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-κB signaling pathway.
Url:
DOI: 10.1172/JCI18714
PubMed: 14523047
PubMed Central: 198529
Affiliations:
- France, Italie, Japon
- Auvergne-Rhône-Alpes, Latium, Rhône-Alpes, Région de Kantō, Île-de-France
- Lyon, Paris, Rome, Tokyo
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PMC:198529Le document en format XML
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<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chable Bessia, Christine" sort="Chable Bessia, Christine" uniqKey="Chable Bessia C" first="Christine" last="Chable-Bessia">Christine Chable-Bessia</name>
<affiliation><nlm:aff id="N0x9488a30.0x95c8070">Unité de Biologie Moléculaire de l’Expression Génique, Centre National de la Recherche Scientifique (CNRS) URA 2582, Institut Pasteur,</nlm:aff>
<wicri:noCountry code="subfield">Institut Pasteur</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yamaoka, Shoji" sort="Yamaoka, Shoji" uniqKey="Yamaoka S" first="Shoji" last="Yamaoka">Shoji Yamaoka</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea> Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo</wicri:regionArea>
<placeName><settlement type="city">Tokyo</settlement>
<region type="région">Région de Kantō</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Feinberg, Jacqueline" sort="Feinberg, Jacqueline" uniqKey="Feinberg J" first="Jacqueline" last="Feinberg">Jacqueline Feinberg</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dupuis Girod, Sophie" sort="Dupuis Girod, Sophie" uniqKey="Dupuis Girod S" first="Sophie" last="Dupuis-Girod">Sophie Dupuis-Girod</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Debrousse, Lyon, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Debrousse, Lyon</wicri:regionArea>
<placeName><region type="region">Auvergne-Rhône-Alpes</region>
<region type="old region">Rhône-Alpes</region>
<settlement type="city">Lyon</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name>
<affiliation><nlm:aff id="N0x9488a30.0x95c8070"> Service de Dermatologie,</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Livadiotti, Susanna" sort="Livadiotti, Susanna" uniqKey="Livadiotti S" first="Susanna" last="Livadiotti">Susanna Livadiotti</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Division of Immunology and Infectious Disease, Children’s Hospital Bambino Gesù, University of Rome Tor Vergata, Rome, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea> Division of Immunology and Infectious Disease, Children’s Hospital Bambino Gesù, University of Rome Tor Vergata, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Novelli, Francesco" sort="Novelli, Francesco" uniqKey="Novelli F" first="Francesco" last="Novelli">Francesco Novelli</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Rossi, Paolo" sort="Rossi, Paolo" uniqKey="Rossi P" first="Paolo" last="Rossi">Paolo Rossi</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Division of Immunology and Infectious Disease, Children’s Hospital Bambino Gesù, University of Rome Tor Vergata, Rome, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea> Division of Immunology and Infectious Disease, Children’s Hospital Bambino Gesù, University of Rome Tor Vergata, Rome</wicri:regionArea>
<placeName><settlement type="city">Rome</settlement>
<region nuts="2">Latium</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fischer, Alain" sort="Fischer, Alain" uniqKey="Fischer A" first="Alain" last="Fischer">Alain Fischer</name>
<affiliation><nlm:aff wicri:cut=", and" id="N0x9488a30.0x95c8070"> Développement Normal et Pathologique du Système Immunitaire, INSERM U429</nlm:aff>
<wicri:noCountry code="subfield">INSERM U429</wicri:noCountry>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Israel, Alain" sort="Israel, Alain" uniqKey="Israel A" first="Alain" last="Israël">Alain Israël</name>
<affiliation><nlm:aff id="N0x9488a30.0x95c8070">Unité de Biologie Moléculaire de l’Expression Génique, Centre National de la Recherche Scientifique (CNRS) URA 2582, Institut Pasteur,</nlm:aff>
<wicri:noCountry code="subfield">Institut Pasteur</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name>
<affiliation><nlm:aff wicri:cut=", and" id="N0x9488a30.0x95c8070"> Unité de Recherches sur les Handicaps Génétiques de l’Enfant, Institut National de la Santé et de la Recherche Médicale (INSERM) U393, Hôpital Necker-Enfants Malades</nlm:aff>
<wicri:noCountry code="subfield">Hôpital Necker-Enfants Malades</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Deist, Francoise Le" sort="Deist, Francoise Le" uniqKey="Deist F" first="Françoise Le" last="Deist">Françoise Le Deist</name>
<affiliation><nlm:aff wicri:cut=", and" id="N0x9488a30.0x95c8070"> Développement Normal et Pathologique du Système Immunitaire, INSERM U429</nlm:aff>
<wicri:noCountry code="subfield">INSERM U429</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="N0x9488a30.0x95c8070"> Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea> Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<imprint><date when="2003">2003</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is
caused by hypomorphic mutations in the gene encoding NEMO/IKKγ, the
regulatory subunit of the IκB kinase (IKK) complex. IKK normally
phosphorylates the IκB-inhibitors of NF-κB at specific
serine residues, thereby promoting their ubiquitination and degradation by the
proteasome. This allows NF-κB complexes to translocate into the
nucleus where they activate their target genes. Here, we describe an
autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense
mutation at serine 32 of IκBα. This mutation is
gain-of-function, as it enhances the inhibitory capacity of
IκBα by preventing its phosphorylation and degradation,
and results in impaired NF-κB activation. The developmental,
immunologic, and infectious phenotypes associated with hypomorphic NEMO and
hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular
responses to ligands of TIR (TLR-ligands, IL-1β, and IL-18), and
TNFR (TNF-α, LTα1/β2, and CD154) superfamily
members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is
associated with a severe and unique T cell immunodeficiency. Despite a marked
blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T
cells do not respond to CD3-TCR activation in vitro. Our report highlights both
the diversity of genotypes associated with EDA-ID and the diversity of
immunologic phenotypes associated with mutations in different components of the
NF-κB signaling pathway.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
<li>Italie</li>
<li>Japon</li>
</country>
<region><li>Auvergne-Rhône-Alpes</li>
<li>Latium</li>
<li>Rhône-Alpes</li>
<li>Région de Kantō</li>
<li>Île-de-France</li>
</region>
<settlement><li>Lyon</li>
<li>Paris</li>
<li>Rome</li>
<li>Tokyo</li>
</settlement>
</list>
<tree><noCountry><name sortKey="Bodemer, Christine" sort="Bodemer, Christine" uniqKey="Bodemer C" first="Christine" last="Bodemer">Christine Bodemer</name>
<name sortKey="Chable Bessia, Christine" sort="Chable Bessia, Christine" uniqKey="Chable Bessia C" first="Christine" last="Chable-Bessia">Christine Chable-Bessia</name>
<name sortKey="Courtois, Gilles" sort="Courtois, Gilles" uniqKey="Courtois G" first="Gilles" last="Courtois">Gilles Courtois</name>
<name sortKey="Deist, Francoise Le" sort="Deist, Francoise Le" uniqKey="Deist F" first="Françoise Le" last="Deist">Françoise Le Deist</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="Smahi, Asma" sort="Smahi, Asma" uniqKey="Smahi A" first="Asma" last="Smahi">Asma Smahi</name>
</noCountry>
<country name="France"><region name="Île-de-France"><name sortKey="Reichenbach, Janine" sort="Reichenbach, Janine" uniqKey="Reichenbach J" first="Janine" last="Reichenbach">Janine Reichenbach</name>
</region>
<name sortKey="Bonnet, Marion" sort="Bonnet, Marion" uniqKey="Bonnet M" first="Marion" last="Bonnet">Marion Bonnet</name>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name>
<name sortKey="Doffinger, Rainer" sort="Doffinger, Rainer" uniqKey="Doffinger R" first="Rainer" last="Döffinger">Rainer Döffinger</name>
<name sortKey="Dupuis Girod, Sophie" sort="Dupuis Girod, Sophie" uniqKey="Dupuis Girod S" first="Sophie" last="Dupuis-Girod">Sophie Dupuis-Girod</name>
<name sortKey="Feinberg, Jacqueline" sort="Feinberg, Jacqueline" uniqKey="Feinberg J" first="Jacqueline" last="Feinberg">Jacqueline Feinberg</name>
<name sortKey="Fischer, Alain" sort="Fischer, Alain" uniqKey="Fischer A" first="Alain" last="Fischer">Alain Fischer</name>
<name sortKey="Novelli, Francesco" sort="Novelli, Francesco" uniqKey="Novelli F" first="Francesco" last="Novelli">Francesco Novelli</name>
<name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name>
</country>
<country name="Italie"><region name="Latium"><name sortKey="Cancrini, Caterina" sort="Cancrini, Caterina" uniqKey="Cancrini C" first="Caterina" last="Cancrini">Caterina Cancrini</name>
</region>
<name sortKey="Livadiotti, Susanna" sort="Livadiotti, Susanna" uniqKey="Livadiotti S" first="Susanna" last="Livadiotti">Susanna Livadiotti</name>
<name sortKey="Rossi, Paolo" sort="Rossi, Paolo" uniqKey="Rossi P" first="Paolo" last="Rossi">Paolo Rossi</name>
</country>
<country name="Japon"><region name="Région de Kantō"><name sortKey="Yamaoka, Shoji" sort="Yamaoka, Shoji" uniqKey="Yamaoka S" first="Shoji" last="Yamaoka">Shoji Yamaoka</name>
</region>
</country>
</tree>
</affiliations>
</record>
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