title: Human X-linked variable immunodeficiency caused by a hypomorphic mutation in XIAP in association with a rare polymorphism in CD40LG.
abstract: 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.
authors.affiliation: Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Inserm, Unité 768, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rigaud
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Granados
authors.forename: Sophie
authors.initials: S
authors.lastname: Sibéril
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gloire
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenoir
authors.forename: Cindy
authors.initials: C
authors.lastname: Synaeve
authors.forename: Maria
authors.initials: M
authors.lastname: Stacey
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Stephan
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000235:genetics; D023201:CD40 Ligand / Q000235:genetics*; D002648:Child; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D004843:Epistasis, Genetic / Q000502:physiology; D005190:Family; D005260:Female; D050172:Genes, X-Linked; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D005973:Glutamine; D023201:CD40 Ligand; D001120:Arginine