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Erschienen in: Journal of Clinical Immunology 8/2022

17.08.2022 | Original Article

Genetic and Functional Identifying of Novel STAT1 Loss-of-Function Mutations in Patients with Diverse Clinical Phenotypes

verfasst von: Xuemei Chen, Junjie Chen, Ran Chen, Huilin Mou, Gan Sun, Lu Yang, Yanjun Jia, Qin Zhao, Wen Wen, Lina Zhou, Yuan Ding, Xuemei Tang, Jun Yang, Yunfei An, Xiaodong Zhao

Erschienen in: Journal of Clinical Immunology | Ausgabe 8/2022

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Abstract

Purpose

Mutations in signal transducer and activator of transcription 1 (STAT1) cause a broad spectrum of disease phenotypes. Heterozygous STAT1 loss-of-function (LOF) mutations cause Mendelian susceptibility to mycobacterial diseases (MSMD) infection, which is attributable to impaired IFN-γ signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency.

Methods

Five patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways.

Results

Four, heterozygous STAT1 deficiency mutations were identified, three of which were novel mutations. Two of the mutations were previously unreported mRNA splicing mutations in AD STAT1-deficient patients. Patients with heterozygous STAT1 deficiency suffered not only mycobacterial infection, but also intracellular non-mycobacterial bacterial infection and congenital multiple malformations. AD-LOF mutation impaired IFN-γ-mediated STAT1 phosphorylation, gamma-activated sequence (GAS), and IFN-stimulated response element (ISRE) transcription activity and IFN-induced gene expression to different extents, which might account for the diverse clinical manifestations observed in these patients.

Conclusion

The infectious disease susceptibility and phenotypic spectrum of patients with AD STAT1-LOF are broader than simply MSMD. The susceptibility to infections and immunological deficiency phenotypes, observed in AD-LOF patients, confirms the importance of STAT1 in host–pathogen interaction and immunity. However, variability in the nature and extent of these phenotypes suggests that functional analysis is required to identify accurately novel, heterozygous STAT1 mutations, associated with pathogenicity. Aberrant splice of STAT1 RNA could result in AD-LOF for STAT1 signaling which need more cases for confirmation.
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Metadaten
Titel
Genetic and Functional Identifying of Novel STAT1 Loss-of-Function Mutations in Patients with Diverse Clinical Phenotypes
verfasst von
Xuemei Chen
Junjie Chen
Ran Chen
Huilin Mou
Gan Sun
Lu Yang
Yanjun Jia
Qin Zhao
Wen Wen
Lina Zhou
Yuan Ding
Xuemei Tang
Jun Yang
Yunfei An
Xiaodong Zhao
Publikationsdatum
17.08.2022
Verlag
Springer US
Erschienen in
Journal of Clinical Immunology / Ausgabe 8/2022
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-022-01339-w

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