Type I Interferonopathy due to a Homozygous Loss-of-Inhibitory Function Mutation in STAT2

Purpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic bas...

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Bibliographic Details
Published in:Journal of clinical immunology 2023-05, Vol.43 (4), p.808-818
Main Authors: Zhu, Gaofeng, Badonyi, Mihaly, Franklin, Lina, Seabra, Luis, Rice, Gillian I., Anne-Boland-Auge, Deleuze, Jean-François, El-Chehadeh, Salima, Anheim, Mathieu, de Saint-Martin, Anne, Pellegrini, Sandra, Marsh, Joseph A., Crow, Yanick J., El-Daher, Marie-Therese
Format: Article
Language:English
Subjects:
Antibodies - genetics
Biochemistry, Molecular Biology
Biomedical and Life Sciences
Biomedicine
Calcification (ectopic)
Fibrosarcoma
Gene Expression Regulation
Genetics
Genomes
Genomics
Homozygote
Human genetics
Humans
Immunofluorescence
Immunology
Immunoprecipitation
Infectious Diseases
Interferon
Interferon Type I - genetics
Internal Medicine
Life Sciences
Medical Microbiology
Mutation
Mutation - genetics
Original
Original Article
Phosphorylation
Signal transduction
Signal Transduction - physiology
STAT1 Transcription Factor - genetics
STAT1 Transcription Factor - metabolism
Stat2 protein
STAT2 Transcription Factor - chemistry
STAT2 Transcription Factor - genetics
Transcriptional Activation
Ubiquitin
Ubiquitin Thiolesterase - genetics
Ubiquitin Thiolesterase - metabolism
USP18 protein
Western blotting
Whole genome sequencing
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Summary:Purpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. Results WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. Conclusion Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.
ISSN:0271-9142
1573-2592
DOI:10.1007/s10875-023-01445-3