Journal of Clinical Immunology

, Volume 32, Issue 4, pp 681–689

A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease

Authors

  • Elizabeth P. Sampaio
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
    • Leprosy Laboratory, Oswaldo Cruz InstituteFIOCRUZ, Manguinhos
  • Hannelore I. Bax
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
    • Department of Internal Medicine and Department of Medical Microbiology and Infectious DiseasesErasmus Medical Center
  • Amy P. Hsu
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Ervand Kristosturyan
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Joseph Pechacek
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Prabha Chandrasekaran
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Michelle L. Paulson
    • Clinical Research Directorate/CMRPSAIC-Frederick, Inc., NCI-Frederick
  • Dalton L. Dias
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Christine Spalding
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Gulbu Uzel
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Li Ding
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
  • Elizabeth McFarland
    • Section of Infectious Diseases, Department of PediatricsChildren’s Hospital Colorado, UC
    • Laboratory of Clinical Infectious DiseasesNIAID, NIH
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