Lars Henrik Fugger

Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Stéphanie Rigaud
  • ,
  • Eduardo Lopez-Granados
  • ,
  • Sophie Sibéril
  • ,
  • Geoffrey Gloire
  • ,
  • Nathalie Lambert
  • ,
  • Christelle Lenoir
  • ,
  • Cindy Synaeve
  • ,
  • Maria Stacey
  • ,
  • Lars Fugger
  • Jean-Louis Stephan
  • ,
  • Alain Fischer
  • ,
  • Capucine Picard
  • ,
  • Anne Durandy
  • ,
  • Helen Chapel
  • ,
  • Sylvain Latour
The present study focuses on a large family with an X-linked immunodeficiency in which there are variable clinical and laboratory phenotypes, including recurrent viral and bacterial infections, hypogammaglobulinemia, Epstein-Barr virus-driven lymphoproliferation, splenomegaly, colitis, and liver disease. Molecular and genetic analyses revealed that affected males were carriers of a hypomorphic hemizygous mutation in XIAP (XIAP(G466X)) that cosegregated with a rare polymorphism in CD40LG (CD40 ligand(G219R)). These genes are involved in the X-linked lymphoproliferative syndrome 2 and the X-linked hyper-IgM syndrome, respectively. Single expression of XIAP(G466X) or CD40L(G219R) had no or minimal effect in vivo, although in vitro, they lead to altered functional activities of their gene products, which suggests that the combination of XIAP and CD40LG mutations contributed to the expression of clinical manifestations observed in affected individuals. Our report of a primary X-linked immunodeficiency of oligogenic origin emphasizes that primary immunodeficiencies are not caused by a single defective gene, which leads to restricted manifestations, but are likely to be the result of an interplay between several genetic determinants, which leads to more variable clinical phenotypes.
Original languageEnglish
JournalIronic Blood
Volume118
Issue2
Pages (from-to)252-61
Number of pages10
ISSN0895-7762
DOIs
Publication statusPublished - 14 Jul 2011

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