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.

journal_name

Blood

journal_title

Blood

authors

Rigaud S,Lopez-Granados E,Sibéril S,Gloire G,Lambert N,Lenoir C,Synaeve C,Stacey M,Fugger L,Stephan JL,Fischer A,Picard C,Durandy A,Chapel H,Latour S

doi

10.1182/blood-2011-01-328849

subject

Has Abstract

pub_date

2011-07-14 00:00:00

pages

252-61

issue

2

eissn

0006-4971

issn

1528-0020

pii

blood-2011-01-328849

journal_volume

118

pub_type

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