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 3

STAT1 P696S would be associated with an ESE defect.

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STAT1 P696S would be associated with an ESE defect. (A) ESE homolog...
(A) ESE homology site in exon 23 predicted by the ESE finder program (25). Nucleotides from exon 23 are shown, with the C2086 nucleotide in the WT sequence and the C2086T substitution in the P696S sequence shown in red. The horizontal blue and green bars show the significance threshold homology score for the binding of SC35 and SRp40 proteins, respectively. The predicted binding sites of these proteins are shown as rectangles along the length of the nucleotide sequence at the height of the homology score. (B) The genomic STAT1 region from nucleotide 36989 to 38523 (NC_000002) was inserted into an exon-trapping vector using XhoI and BamH1, with or without the C2086T (P696S) nucleotide substitution. The exons are numbered in Roman numerals and shown in gray boxes, with the introns between them in white boxes, with the exception of exon 23, which is shown in a red box. The vector is shown as black boxes. HEK293 and COS-7 cells were transfected with the various constructs, the exon-trapping pSPL3 mock vector (pmock-p), or no vector (–). RNA was isolated, and the various spliced products were amplified and are shown on an agarose gel with GADPH amplification. The various products were isolated and sequenced, and the resulting sequences are also shown with corresponding exons and MW. These results are representative of 2 independent experiments.