A Novel Gain-of-Function IKBA Mutation Underlies Ectodermal Dysplasia with Immunodeficiency and Polyendocrinopathy

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• 作者：Lena F. Schimke (1) (2)
  Nikolaus Rieber (2) (3)
  Stacey Rylaarsdam (1)
  Otávio Cabral-Marques (1) (4)
  Nicholas Hubbard (1)
  Anne Puel (5) (6)
  Laura Kallmann (2)
  Stephanie Anover Sombke (1)
  Gundula Notheis (2)
  Hans-Peter Schwarz (2)
  Birgit Kammer (2)
  Tomas H?kfelt (7)
  Reinald Repp (8)
  Capucine Picard (5) (6) (9)
  Jean-Laurent Casanova (10) (5) (6)
  Bernd H. Belohradsky (2)
  Michael H. Albert (2)
  Hans D. Ochs (1)
  Ellen D. Renner (11)
  Troy R. Torgerson (1)
  
• 关键词：Ectodermal dysplasia with immunodeficiency ; IKBA ; NF ; κB signaling ; polyendocrinopathy
• 刊名：Journal of Clinical Immunology
• 出版年：2013
• 出版时间：August 2013
• 年：2013
• 卷：33
• 期：6
• 页码：1088-1099
• 全文大小：527KB
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• 作者单位：Lena F. Schimke (1) (2)
  Nikolaus Rieber (2) (3)
  Stacey Rylaarsdam (1)
  Otávio Cabral-Marques (1) (4)
  Nicholas Hubbard (1)
  Anne Puel (5) (6)
  Laura Kallmann (2)
  Stephanie Anover Sombke (1)
  Gundula Notheis (2)
  Hans-Peter Schwarz (2)
  Birgit Kammer (2)
  Tomas H?kfelt (7)
  Reinald Repp (8)
  Capucine Picard (5) (6) (9)
  Jean-Laurent Casanova (10) (5) (6)
  Bernd H. Belohradsky (2)
  Michael H. Albert (2)
  Hans D. Ochs (1)
  Ellen D. Renner (11)
  Troy R. Torgerson (1)
  
  1. Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, WA, 98101-1304, USA
  2. Dr. Von Haunersches Kinderspital, Ludwig Maximilians University, Munich, Germany
  3. Department of Pediatrics I, University of Tübingen, Tübingen, Germany
  4. Department of Immunology, University of Sao Paulo, Sao Paulo, Brazil
  5. Human Genetics of Infectious Diseases, INSERM U980, Necker Medical School, Paris, France
  6. Paris Descartes University, Paris Sorbonne Cité, France
  7. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  8. Children’s Hospital, Fulda, Germany
  9. Study Center of Primary Immunodeficiencies, Assistance Publique H?pitaux de Paris, Necker Hospital, Paris, France
  10. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA
  11. Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, Ludwig Maximilians Universit?t, Lindwurmstr. 4, D-80337, München, Germany
  

文摘

Purpose This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. Methods NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. Results Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17?T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1?, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. Conclusion The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.