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

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

doi:10.1038/s41525-018-0063-6

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

NPJ Genom Med. 2018 Aug 20:3:23. doi: 10.1038/s41525-018-0063-6. eCollection 2018.

Authors

Adi Ovadia^{1

2}, Nigel Sharfe^{1

2}, Cynthia Hawkins³, Suzanne Laughlin⁴, Chaim M Roifman^{1

2}

Affiliations

¹ 1Division of Immunology and Allergy, Department of Paediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, ON Canada.
² 2The Canadian Center for Primary Immunodeficiency and The Jeffrey Modell Research Laboratory for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children and The University of Toronto, Toronto, ON Canada.
³ 3Department of Laboratory Medicine & Pathobiology, The Hospital for Sick Children, Toronto, ON Canada.
⁴ 4Department of Radiology, The Hospital for Sick Children, Toronto, ON Canada.

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.

Publication types

Case Reports