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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

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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 4

Only the normal splicing STAT1P696S form is translated.

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Only the normal splicing STAT1P696S form is translated.
   
Human cells ...
Human cells completely lacking STAT1 (U3C cells) were transfected with the WTα, P696SαA, and P696SαB STAT1 alleles or with the V5-tagged vector containing a mock allele (pmock-V5) or were not transfected (–). (A) These cells were subjected to Western blotting analysis with specific STAT1 and STAT2 antibodies; (B) subjected to full-length PCR amplification of the STAT1A isoform and ACTIN cDNAs; and (C) subjected to relative real-time STAT1 PCR. The results were normalized with respect to GUS mRNA and are expressed as a percentage of the amount of WT STAT1 mRNA. SD from triplication of a single experiment is indicated. These results are representative of 2 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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