A novel STAT1 loss-of-function mutation associated with Mendelian susceptibility to mycobacterial disease

Ye, Fanghua; Zhang, Wen; Dong, Jiajia; Peng, Min; Fan, Chenying; Deng, Wenjun; Zhang, Hui; Yang, Lian-Yue

doi:10.3389/fcimb.2022.1002140

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…Autosomal dominant STAT1 deficiency dominant negative mutations confer loss of function 13 . Dominant negative (DN) mutations result in the generation of a mutated protein that interferes with the activity of the wild type protein, resulting in loss of protein activity.…”

Section: Stat1‐related Diseasementioning

confidence: 99%

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices

Chaimowitz,

Smith,

Forbes Satter

2024

Immunological Reviews

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SummaryInborn errors of immunity (IEIs) encompass a diverse spectrum of genetic disorders that disrupt the intricate mechanisms of the immune system, leading to a variety of clinical manifestations. Traditionally associated with an increased susceptibility to recurrent infections, IEIs have unveiled a broader clinical landscape, encompassing immune dysregulation disorders characterized by autoimmunity, severe allergy, lymphoproliferation, and even malignancy. This review delves into the intricate interplay between IEIs and the JAK–STAT signaling pathway, a critical regulator of immune homeostasis. Mutations within this pathway can lead to a wide array of clinical presentations, even within the same gene. This heterogeneity poses a significant challenge, necessitating individually tailored therapeutic approaches to effectively manage the diverse manifestations of these disorders. Additionally, JAK–STAT pathway defects can lead to simultaneous susceptibility to both infection and immune dysregulation. JAK inhibitors, with their ability to suppress JAK–STAT signaling, have emerged as powerful tools in controlling immune dysregulation. However, questions remain regarding the optimal selection and dosing regimens for each specific condition. Hematopoietic stem cell transplantation (HSCT) holds promise as a curative therapy for many JAK–STAT pathway disorders, but this procedure carries significant risks. The use of JAK inhibitors as a bridge to HSCT has been proposed as a potential strategy to mitigate these risks.

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Section: Stat1‐related Diseasementioning

confidence: 99%

JAK/STAT defects and immune dysregulation, and guiding therapeutic choices

Chaimowitz,

Smith,

Forbes Satter

2024

Immunological Reviews

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“…Since 2001, 31 patients with autosomal dominant STAT1 deficiency have been documented [ 144 , 154 ]. They show heterozygous mutations in the DNA binding domain [ 155 ], the SH 2 domain [ 156 , 157 ], or the tyrosine residue Y701 [ 158 ], which is mainly responsible for the activation of the protein through phosphorylation.…”

Section: Biallelic and Heterozygous Stat1 Loss-of-...mentioning

confidence: 99%

JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

et al. 2023

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The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway’s architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.

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