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Science 293 (5528): 300-303

Copyright © 2001 by the American Association for the Advancement of Science

Impairment of Mycobacterial But Not Viral Immunity by a Germline Human STAT1 Mutation

Stéphanie Dupuis,12 Catherine Dargemont,3 Claire Fieschi,1 Nicolas Thomassin,4 Sergio Rosenzweig,5 Jeff Harris,6 Steven M. Holland,5 Robert D. Schreiber,7 Jean-Laurent Casanova18*

Interferons (IFN) alpha /beta and gamma  induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.

1 Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM UMR550, Faculté de Médecine Necker-Enfants Malades, 75015 Paris, France.
2 INSERM U429, Hôpital Necker-Enfants Malades, 75015 Paris, France.
3 Institut Jacques Monod, CNRS-Université Paris VI-Université Paris VII- CNRS UMR7592, 75005 Paris, France.
4 Departement de Pédiatrie, Centre Hospitalier Général, 58000 Nevers, France.
5 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-1886, USA.
6 Department of Pediatrics, University of California at San Francisco, San Francisco, CA 94117, USA.
7 Department of Pathology, Washington University, St. Louis, MO 63110, USA.
8 Unité d'Hématologie-Immunologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
*   To whom correspondence should be addressed. E-mail: casanova{at}necker.fr

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