Two different STAT1 gain-of-function mutations lead to diverse IFN-\u03b3-mediated gene expression

Adi Ovadia,Cynthia Hawkins,Nigel Sharfe,Suzanne Laughlin,Chaim M Roifman

doi:10.1038/s41525-018-0063-6

Abstract

Signal transducer and activator of transcription 1 (STAT1) regulates multiple biological processes downstream of a variety of cytokine receptors in many cell types. Heterozygous gain-of-function (GOF) mutations in STAT1 have been associated with a diverse phenotype encompassing chronic mucocutaneous candidiasis (CMCC) and declining immunity. There is no clear correlation between STAT1 domain-specific mutations and phenotype, and it remains unclear why GOF mutations in STAT1 result in such a wide spectrum of clinical presentations. To begin exploring this dilemma, we have studied the patterns of gene expression mediated by two different GOF mutations. Analysis of IFN-γ response elements using RNA microarrays in cells transfected with the rare H629Y mutant or the common R274G mutant showed distinct patterns of gene expression. We show here that the impact of GOF mutations in STAT1 is variant-specific. This difference in gene expression may explain the diversity in clinical manifestations experienced by these patients.

Highlights

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that controls many biological effects downstream of the type I interferons as well as other cytokine receptors in many cell types.[1]Monoallelic mutations in STAT1 have been identified in patients with a great diversity of clinical manifestations and immune lesions
Mutations have been predominately associated with chronic mucocutaneous candidiasis (CMCC)[2,3] with or without a variety of autoimmune manifestations.[4,5]
STAT1 mutations have been associated with a gradual decline in cellular and humoral immunity leading to fatal viral infections.[6]

Summary

Introduction

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that controls many biological effects downstream of the type I interferons as well as other cytokine receptors in many cell types.[1]Monoallelic mutations in STAT1 have been identified in patients with a great diversity of clinical manifestations and immune lesions. In order to understand why this patient has such a unique clinical pattern we studied gene expression patterns triggered by this mutation and compared it to the common mutant R274G, both designated GOF mutations. We found increased STAT1 phosphorylation in H629Ymutated patient T cells following IFN-α and IL-27 stimulation (Fig. 2b, c).

Results

Conclusion