Journal of Clinical Immunology

, Volume 32, Issue 4, pp 681–689

A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease

  • Elizabeth P. Sampaio
  • Hannelore I. Bax
  • Amy P. Hsu
  • Ervand Kristosturyan
  • Joseph Pechacek
  • Prabha Chandrasekaran
  • Michelle L. Paulson
  • Dalton L. Dias
  • Christine Spalding
  • Gulbu Uzel
  • Li Ding
  • Elizabeth McFarland
  • Steven M. Holland
Article

DOI: 10.1007/s10875-012-9659-2

Cite this article as:
Sampaio, E.P., Bax, H.I., Hsu, A.P. et al. J Clin Immunol (2012) 32: 681. doi:10.1007/s10875-012-9659-2

Abstract

STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.

Keywords

STAT1SH2 domainmycobacterial diseaseIFN-γ

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Elizabeth P. Sampaio
    • 1
    • 2
  • Hannelore I. Bax
    • 1
    • 3
  • Amy P. Hsu
    • 1
  • Ervand Kristosturyan
    • 1
  • Joseph Pechacek
    • 1
  • Prabha Chandrasekaran
    • 1
  • Michelle L. Paulson
    • 4
  • Dalton L. Dias
    • 1
  • Christine Spalding
    • 1
  • Gulbu Uzel
    • 1
  • Li Ding
    • 1
  • Elizabeth McFarland
    • 5
  • Steven M. Holland
    • 1
    • 6
  1. 1.Laboratory of Clinical Infectious DiseasesNIAID, NIHBethesdaUSA
  2. 2.Leprosy Laboratory, Oswaldo Cruz InstituteFIOCRUZ, ManguinhosRio de JaneiroBrazil
  3. 3.Department of Internal Medicine and Department of Medical Microbiology and Infectious DiseasesErasmus Medical CenterRotterdamthe Netherlands
  4. 4.Clinical Research Directorate/CMRPSAIC-Frederick, Inc., NCI-FrederickFrederickUSA
  5. 5.Section of Infectious Diseases, Department of PediatricsChildren’s Hospital Colorado, UCDenverUSA
  6. 6.BethesdaUSA