A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency
Identifieur interne : 002725 ( Pmc/Curation ); précédent : 002724; suivant : 002726A 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
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Gilles Courtois<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>
<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>
<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>
<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="1"><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>
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<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>
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<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>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A hypermorphic IκBα mutation is associated
with autosomal dominant anhidrotic ectodermal dysplasia and T cell
immunodeficiency</title>
<author><name sortKey="Courtois, Gilles" sort="Courtois, Gilles" uniqKey="Courtois G" first="Gilles" last="Courtois">Gilles Courtois</name>
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<wicri:noCountry code="subfield">Institut Pasteur</wicri:noCountry>
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<author><name sortKey="Smahi, Asma" sort="Smahi, Asma" uniqKey="Smahi A" first="Asma" last="Smahi">Asma Smahi</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>
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<author><name sortKey="Reichenbach, Janine" sort="Reichenbach, Janine" uniqKey="Reichenbach J" first="Janine" last="Reichenbach">Janine Reichenbach</name>
<affiliation wicri:level="1"><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>
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<author><name sortKey="Doffinger, Rainer" sort="Doffinger, Rainer" uniqKey="Doffinger R" first="Rainer" last="Döffinger">Rainer Döffinger</name>
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<wicri:regionArea> Division of Immunology and Infectious Disease, Children’s Hospital Bambino Gesù, University of Rome Tor Vergata, Rome</wicri:regionArea>
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<author><name sortKey="Bonnet, Marion" sort="Bonnet, Marion" uniqKey="Bonnet M" first="Marion" last="Bonnet">Marion Bonnet</name>
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<country xml:lang="fr">France</country>
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<author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name>
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<country xml:lang="fr">France</country>
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<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>
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<author><name sortKey="Yamaoka, Shoji" sort="Yamaoka, Shoji" uniqKey="Yamaoka S" first="Shoji" last="Yamaoka">Shoji Yamaoka</name>
<affiliation wicri:level="1"><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>
</affiliation>
</author>
<author><name sortKey="Feinberg, Jacqueline" sort="Feinberg, Jacqueline" uniqKey="Feinberg J" first="Jacqueline" last="Feinberg">Jacqueline Feinberg</name>
<affiliation wicri:level="1"><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>
</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="1"><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>
</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="1"><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>
</affiliation>
</author>
<author><name sortKey="Novelli, Francesco" sort="Novelli, Francesco" uniqKey="Novelli F" first="Francesco" last="Novelli">Francesco Novelli</name>
<affiliation wicri:level="1"><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>
</affiliation>
</author>
<author><name sortKey="Rossi, Paolo" sort="Rossi, Paolo" uniqKey="Rossi P" first="Paolo" last="Rossi">Paolo Rossi</name>
<affiliation wicri:level="1"><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>
</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="1"><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>
</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="1"><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>
</affiliation>
<affiliation wicri:level="1"><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>
</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>
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<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>
<pmc article-type="research-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id>
<journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id>
<journal-title>The Journal of Clinical Investigation</journal-title>
<issn pub-type="ppub">0021-9738</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">14523047</article-id>
<article-id pub-id-type="pmc">198529</article-id>
<article-id pub-id-type="publisher-id">18714</article-id>
<article-id pub-id-type="doi">10.1172/JCI18714</article-id>
<article-id pub-id-type="pmcid">198529</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>A hypermorphic IκBα mutation is associated
with autosomal dominant anhidrotic ectodermal dysplasia and T cell
immunodeficiency</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Courtois</surname>
<given-names>Gilles</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smahi</surname>
<given-names>Asma</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Reichenbach</surname>
<given-names>Janine</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Döffinger</surname>
<given-names>Rainer</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cancrini</surname>
<given-names>Caterina</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bonnet</surname>
<given-names>Marion</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Puel</surname>
<given-names>Anne</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chable-Bessia</surname>
<given-names>Christine</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yamaoka</surname>
<given-names>Shoji</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feinberg</surname>
<given-names>Jacqueline</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dupuis-Girod</surname>
<given-names>Sophie</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bodemer</surname>
<given-names>Christine</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Livadiotti</surname>
<given-names>Susanna</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Novelli</surname>
<given-names>Francesco</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rossi</surname>
<given-names>Paolo</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fischer</surname>
<given-names>Alain</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">8</xref>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Israël</surname>
<given-names>Alain</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Munnich</surname>
<given-names>Arnold</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deist</surname>
<given-names>Françoise Le</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Casanova</surname>
<given-names>Jean-Laurent</given-names>
</name>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">3</xref>
<xref ref-type="aff" rid="N0x9488a30.0x95c8070">9</xref>
</contrib>
</contrib-group>
<aff id="N0x9488a30.0x95c8070"><label>1</label>
Unité de Biologie Moléculaire de l’Expression Génique, Centre National de la Recherche Scientifique (CNRS) URA 2582, Institut Pasteur,<label>2</label>
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, and<label>3</label>
Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker-Enfants Malades, Paris, France<label>4</label>
Division of Immunology and Infectious Disease, Children’s Hospital Bambino Gesù, University of Rome Tor Vergata, Rome, Italy<label>5</label>
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan<label>6</label>
Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Debrousse, Lyon, France<label>7</label>
Service de Dermatologie,<label>8</label>
Développement Normal et Pathologique du Système Immunitaire, INSERM U429, and<label>9</label>
Unité d’Immunologie et d’Hématologie Pédiatriques, Hôpital Necker-Enfants Malades, Paris, France</aff>
<author-notes><fn><p>Address correspondence to: Jean-Laurent Casanova, Laboratoire de
Génétique Humaine des Maladies Infectieuses,
Université de Paris René Descartes-INSERM U550,
Faculté de Médecine Necker-Enfants Malades, 156 rue
de Vaugirard, 75015 Paris, France. Phone: 33-1-40-61-53-81; Fax:
33-1-40-61-56-88; E-mail: <email>casanova@necker.fr</email>
.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>1</day>
<month>10</month>
<year>2003</year>
</pub-date>
<volume>112</volume>
<issue>7</issue>
<fpage>1108</fpage>
<lpage>1115</lpage>
<copyright-statement>Copyright © 2003, American Society for Clinical
Investigation</copyright-statement>
<copyright-year>2003</copyright-year>
<abstract><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>
</abstract>
</article-meta>
</front>
<floats-wrap><fig id="F1" position="float"><label>Figure 1</label>
<caption><p>Defective NF-κB activation in patient’s fibroblasts.
(<bold>a</bold>
) EMSA after exposure to 10 ng/ml TNF-α. The
composition of the retarded species is indicated on the right and was
determined as described in Smahi et al. (<xref rid="B10" ref-type="bibr">10</xref>
). C, control fibroblasts; P, fibroblasts from patient under
study; X-EDA-ID, patient with OL-EDA-ID fibroblasts. (<bold>b</bold>
)
Western blot analysis of cytoplasmic RelA, p105, and p50.(<bold>c</bold>
)
Analysis of IL-6 synthesis by primary fibroblasts from patients and a
healthy control. Cells were treated overnight with 10 ng/ml of
TNF-α or IL-1β, and IL-6 secretion was measured in
the supernatant using ELISA. Results from one representative experiment are
shown. (<bold>d</bold>
) Analysis of IL-6 synthesis by SV-40-transformed
fibroblasts from patients and a healthy control. Cells were treated for 24
hours with 50 ng/ml of LTα1/β2, and IL-6 secretion
was measured in the supernatant using ELISA. Results from one representative
experiment are shown.</p>
</caption>
<graphic xlink:href="JCI0318714.f1"></graphic>
</fig>
<fig id="F2" position="float"><label>Figure 2</label>
<caption><p>Specific defect of IκBα degradation in
patient’s fibroblasts treated with TNF-α
(<bold>a</bold>
) IKK kinase assay and Western blot analysis of
IκBα degradation. Phosphorylated
IκBα exhibits a retarded migration and is indicated
on the right. GST-IκBα, a fusion between
gluthatione-S-Transferase and the first 72 amino acids of
IκBα, was used as a substrate for IKK. GST,
gluthatione-S-transferase. (<bold>b</bold>
) Western blot analysis of IKK
subunits in fibroblasts from a healthy control, NEMO-mutated patient
X-EDA-ID and IκBα-mutated patient P.
(<bold>c</bold>
) Western blot analysis of IκBα Ser32
phosphorylation after TNF-α stimulation. Circled P,
phosphorylated. (<bold>d</bold>
) Time course analysis of TNF-induced
IκBα, IκBβ, and
IκBε degradation, as detected by Western blot.
Results from one representative experiment are shown.</p>
</caption>
<graphic xlink:href="JCI0318714.f2"></graphic>
</fig>
<fig id="F3" position="float"><label>Figure 3</label>
<caption><p>Sequence of the <italic>IKBA</italic>
gene in the patient and his relatives.
(<bold>a</bold>
) Schematic representation of
IκBα. The various functional/structural domains of
the protein are shown. NH2, N-terminal; rPEST, repeated peptidic sequence
rich in proline, glutamic acide, serine, and threonine (PEST); Ile,
isoleucine. (<bold>b</bold>
) Phosphoacceptor sites of IκB
molecules and location of the patient’s mutation S32I. The two
conserved serine residues that are phosphorylated by IKK in
IκBα, IκBβ, and
IκBε are boxed. Mutated Ser32 of patient P is
indicated by an arrow. (<bold>c</bold>
) Automated sequencing profile of
genomic DNA showing the heterozygous C/T polymorphism at position 89 and the
heterozygous G/T (S32I) disease-causing mutation at position 94 in our
patient. The two heterozygous positions from left (position 89) to right
(position 94) appear as N nucleotides.</p>
</caption>
<graphic xlink:href="JCI0318714.f3"></graphic>
</fig>
<fig id="F4" position="float"><label>Figure 4</label>
<caption><p>Dominant effect of the S32I <italic>IKBA</italic>
mutation on
NF-κB activation. HEK 293T cells were transfected with
Igκ-luc, a reporter plasmid for NF-κB, and either an
empty expression vector (control) or an expression vector encoding WT
IκBα (WT), the S32I mutant or the S32A/S36A double
mutant. Twenty-four hours later, the cells were stimulated with
TNF-α. The relative expression of IκBα
molecules is shown at the bottom, as detected by Western blotting.</p>
</caption>
<graphic xlink:href="JCI0318714.f4"></graphic>
</fig>
<fig id="F5" position="float"><label>Figure 5</label>
<caption><p>PBMC and T cell analysis. (<bold>a</bold>
) Peripheral blood cells from
patient P, a healthy control, and patient X-EDA-ID with OL-EDA-ID were
stimulated by PHA, PMA-ionomycin, IL-12, IL-12 +
IL-1β, or PHA, and IFN-γ secretion was measured by
ELISA. Results from one representative experiment are shown.
(<bold>b</bold>
) Peripheral blood cells were stimulated by PMA-ionomycin or
LPS + IFN-γ, and TNF-α secretion was
measured by ELISA. Results from one representative experiment are shown.
(<bold>c</bold>
) CD45RA and CD45RO expression on control (C) and patient
(P) T cells at day 0 and day 10 of PHA + IL-2 stimulation in
vitro, as detected by flow cytometry. (<bold>d</bold>
) T cell proliferation
(left) after 64 hours of stimulation with anti-CD3 alone, or anti-CD3 in
combination with anti-CD28. Production of IFN-γ (right) in
culture supernatants after 48 hours of stimulation with anti-CD3 alone or in
combination with anti-CD28. Results from one representative experiment are
shown. Data are normalized for 10<sup>6</sup>
cells.</p>
</caption>
<graphic xlink:href="JCI0318714.f5"></graphic>
</fig>
<table-wrap id="T1" position="float"><label>Table 1</label>
<caption><p>Lymphocytes subsets in the blood</p>
</caption>
<graphic xlink:href="JCI0318714.t1"></graphic>
</table-wrap>
<table-wrap id="T2" position="float"><label>Table 2</label>
<caption><p>T cell proliferation in vitro</p>
</caption>
<graphic xlink:href="JCI0318714.t2"></graphic>
</table-wrap>
</floats-wrap>
</pmc>
</record>
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