A partial form of recessive STAT1 deficiency in humans
Ariane Chapgier, … , Dan Engelhard, Jean-Laurent Casanova
Ariane Chapgier, … , Dan Engelhard, Jean-Laurent Casanova
Published May 11, 2009
Citation Information: J Clin Invest. 2009;119(6):1502-1514. https://doi.org/10.1172/JCI37083.
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Research Article Immunology

A partial form of recessive STAT1 deficiency in humans

Abstract

Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-α/β and IFN-γ. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-α/β and IFN-γ signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients’ cells, therefore, displayed impaired but not abolished responses to both IFN-α and IFN-γ. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-λ1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-α/β, IFN-γ, IFN-λ1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.

Authors

Ariane Chapgier, Xiao-Fei Kong, Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy, Diana Averbuch, Jacqueline Feinberg, Shen-Ying Zhang, Jacinta Bustamante, Guillaume Vogt, Julien Lejeune, Eleonore Mayola, Ludovic de Beaucoudrey, Laurent Abel, Dan Engelhard, Jean-Laurent Casanova

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Figure 1

STAT1 P696S is associated with salmonellosis and viral disease.

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STAT1 P696S is associated with salmonellosis and viral disease. (A)...
(A) Human STAT1a and STAT1b isoforms are shown, with their known pathogenic mutations. Coding exons are numbered with Roman numerals and delimited by a vertical bar. Regions corresponding to the coiled-coil domain (CC), DNA-binding domain (DNA-B), linker domain (L), SH2 domain (SH2), tail segment domain (TS), and transactivator domain (TA) are indicated in gray, together with their amino acid boundaries, and are delimited by gray dotted lines. Tyr701 (Y) and Ser727 (S) are indicated. Mutations in red are recessive and associated with complete STAT1 deficiency in homozygous individuals. Mutations in green are associated with partial STAT1 deficiency in heterozygous individuals. The mutation in blue is a partial recessive mutation associated with partial STAT1 deficiency in homozygous individuals. The mutation reported here for what we believe to be the first time is indicated in italics. (B) STAT1 genotype and clinical phenotype of the kindred. Members II.1 and II.3 presented salmonellosis, and II.3 also presented viral diseases. These 2 individuals are subsequently referred to as P1 and P2, respectively. Individuals with clinical disease are indicated in black, and healthy individuals are shown in white. The mother, who is heterozygous for the STAT1 P696S mutation, is subsequently referred to as H. STAT1 genotypes are indicated under each individual. The index case is indicated with an arrow. (C) Genomic sequences in the sense orientation of exon 23 of STAT1 in a healthy control and in P1. C+/+ indicates a healthy control.