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J Infect Dis. 2017 Dec 19;216(12):1623-1634. doi: 10.1093/infdis/jix522.

Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-γ Immunity.

Author information

1
Department of Immunology, University of Sao Paulo, Brazil.
2
Department of Rheumatology and Clinical Immunology, University of Lübeck, Germany.
3
Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, New York.
4
St Giles Laboratory of Human Genetics of Infectious Diseases, the Rockefeller University, New York.
5
Tropical Diseases Area, Botucatu Medical School, São Paulo State University, Brazil.
6
Laboratory of Biochemistry and Biophysics, Butantan Institute, Sao Paulo, Brazil.
7
Human Genome and Stem Cell Research Center, University of Sao Paulo, Brazil.
8
Imagine Institute, Paris Descartes University, Paris, France.
9
Laboratory of Human Genetics of Infectious Diseases, Paris, France.
10
Center for the Study of Primary Immunodeficiencies, Paris, France.
11
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
12
Howard Hughes Medical Institute, the Rockefeller University, New York.
13
Institute of Tropical Medicine, University of Sao Paulo, Brazil.

Abstract

Background:

Mutations in genes affecting interferon-γ (IFN-γ) immunity have contributed to understand the role of IFN-γ in protection against intracellular pathogens. However, inborn errors in STAT4, which controls interleukin-12 (IL-12) responses, have not yet been reported. Our objective was to determine the genetic defect in a family with a history of paracoccidioidomycosis.

Methods:

Genetic analysis was performed by whole-exome sequencing and Sanger sequencing. STAT4 phosphorylation (pSTAT4) and translocation to the nucleus, IFN-γ release by patient lymphocytes, and microbicidal activity of patient monocytes/macrophages were assessed. The effect on STAT4 function was evaluated by site-directed mutagenesis using a lymphoblastoid B cell line (B-LCL) and U3A cells.

Results:

A heterozygous missense mutation, c.1952 A>T (p.E651V) in STAT4 was identified in the index patient and her father. Patient's and father's lymphocytes showed reduced pSTAT4, nuclear translocation, and impaired IFN-γ production. Mutant B-LCL and U3A cells also displayed reduced pSTAT4. Patient's and father's peripheral blood mononuclear cells and macrophages demonstrated impaired fungicidal activity compared with those from healthy controls that improved in the presence of recombinant human IFN-γ, but not rhIL-12.

Conclusion:

Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-γ immunity associated with susceptibility to paracoccidioidomycosis.

KEYWORDS:

IL-12/IFN-γ axis; STAT4 deficiency; paracoccidioidomycosis; primary immunodeficiency

PMID:
29029192
DOI:
10.1093/infdis/jix522
[Indexed for MEDLINE]

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