Human inherited complete STAT2 deficiency underlies inflammatory viral diseases
Giorgia Bucciol, … , Jean-Laurent Casanova, Isabelle Meyts
Giorgia Bucciol, … , Jean-Laurent Casanova, Isabelle Meyts
Published March 28, 2023
Citation Information: J Clin Invest. 2023;133(12):e168321. https://doi.org/10.1172/JCI168321.
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Research Article Immunology

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases

Abstract

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients’ cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival.

Authors

Giorgia Bucciol, Leen Moens, Masato Ogishi, Darawan Rinchai, Daniela Matuozzo, Mana Momenilandi, Nacim Kerrouche, Catherine M. Cale, Elsa R. Treffeisen, Mohammad Al Salamah, Bandar K. Al-Saud, Alain Lachaux, Remi Duclaux-Loras, Marie Meignien, Aziz Bousfiha, Ibtihal Benhsaien, Anna Shcherbina, Anna Roppelt, COVID Human Genetic Effort, Florian Gothe, Nadhira Houhou-Fidouh, Scott J. Hackett, Lisa M. Bartnikas, Michelle C. Maciag, Mohammed F. Alosaimi, Janet Chou, Reem W. Mohammed, Bishara J. Freij, Emmanuelle Jouanguy, Shen-Ying Zhang, Stephanie Boisson-Dupuis, Vivien Béziat, Qian Zhang, Christopher J.A. Duncan, Sophie Hambleton, Jean-Laurent Casanova, Isabelle Meyts

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Figure 1

STAT2 variants in 10 kindreds with severe viral infections.

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STAT2 variants in 10 kindreds with severe viral infections. (A) Pedigre...
(A) Pedigrees of the 10 STAT2-deficient kindreds. Double lines connecting parents indicate consanguinity. Filled symbols indicate individuals with biallelic mutations, and half-filled symbols indicate carriers of heterozygous mutations. M, mutated allele; ?, unknown genotype. (B) Schematic illustration of the STAT2 gene with 22 coding exons and of the STAT2 protein with its domains. N, N-terminal domain; CC, coiled-coil domain; DBD, DNA-binding domain; L, linker domain; SH2, Scr homology 2 domain; P-Y690, tyrosine phosphorylation site; TAD, transcriptional activation domain. All previously reported and new STAT2 variants are indicated. (C) Population genetics of homozygous coding missense and pLOF STAT2 mutations from gnomAD and in-house cohorts. The patients’ variants are private and shown in red, whereas the 8 variants detected in gnomAD are shown in black. CADD, combined annotation-dependent depletion; MSC, mutation significance cutoff.