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 2

STAT1 P696S is associated with a predominant splicing defect.

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STAT1 P696S is associated with a predominant splicing defect. (A) P...
(A) PCR of full-length STAT1A, STAT1B, and ACTIN amplified from cDNA from C+/+, P1 (homozygous for the P696S STAT1 mutation), and H. The sizes of the amplicons are indicated. This result is representative of 5 independent experiments. (B) Schematic representation of the splicing events identified in STAT1A and STAT1B WT or P696S mutant. The ends of the WT and P696S STAT1 mRNAs are shown, with their corresponding spliced forms. The exons are numbered with Roman numerals and represented in gray boxes, with the introns between them shown in white boxes, with the exception of exon 23, shown in red and purple boxes in the α and β isoforms, respectively. The hatched bars at the beginning of each sequence represent the 5′ region of each mRNA. At the end of the STAT1A form, the hatched red bars represent the STAT1A polyadenylation site at the end of exon 25. At the end of STAT1B forms, the hatched purple bars represent the STAT1B polyadenylation site at the end of exon 23, which is longer than STAT1A exon 23. The open brackets represent the splicing events. Events shown in red predominate and are associated with the P696S STAT1 mutation.