Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16463-16472. doi: 10.1073/pnas.1901409116. Epub 2019 Jul 25.

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France.
2
Imagine Institute, Paris Descartes University, 75015 Paris, France.
3
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
4
Research Branch, Sidra Medicine, Qatar Foundation, Doha, Qatar.
5
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.
6
Proteomic Center, The Rockefeller University, New York, NY 10065.
7
Study Center for Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
8
Internal Medicine Unit, Grenoble Hospital, 38043 Grenoble, France.
9
Pneumology Unit, Louis Pradel Hospital, 69500 Bron, France.
10
Infectious Diseases Unit, Necker Hospital for Sick Children, AP-HP, 75015 Paris, France.
11
Molecular Mycology Unit, National Reference Center for Invasive Fungal Infections, CNRS UMR 2000, Pasteur Institute, 75015 Paris, France.
12
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065.
13
College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
14
St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
15
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, 75015 Paris, France; casanova@rockefeller.edu bebo283@rockefeller.edu.
16
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.

Abstract

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

KEYWORDS:

STAT3; dominant negative; hyper IgE syndrome; immunodeficiency; infectious diseases

PMID:
31346092
PMCID:
PMC6697804
[Available on 2020-01-25]
DOI:
10.1073/pnas.1901409116

Conflict of interest statement

Conflict of interest statement: S.G.T., J.D.M., and M.A.C. are coauthors on a 2017 Letter to the Editor. C.P., A.P., J.-L.C., and J.D.M. are coauthors of a 2016 research article (PMID: 27114460); C.P., A.P., and J.-L.C. did not collaborate actively with J.D.M. for this article.

Supplemental Content

Full text links

Icon for HighWire Icon for Rockefeller University Rita and Frits Markus Library
Loading ...
Support Center