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The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants.
Chen, Yin-Huai; van Zon, Sarah; Adams, Alex; Schmidt-Arras, Dirk; Laurence, Arian D J; Uhlig, Holm H.
Afiliación
  • Chen YH; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • van Zon S; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Adams A; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Schmidt-Arras D; Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria.
  • Laurence ADJ; Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
  • Uhlig HH; Translational Gastroenterology Unit, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
J Clin Immunol ; 44(1): 30, 2023 12 22.
Article en En | MEDLINE | ID: mdl-38133879
ABSTRACT
Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Interleucina-11 / Receptor gp130 de Citocinas / Síndrome de Job Límite: Humans Idioma: En Revista: J Clin Immunol Año: 2023 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Interleucina-11 / Receptor gp130 de Citocinas / Síndrome de Job Límite: Humans Idioma: En Revista: J Clin Immunol Año: 2023 Tipo del documento: Article