STAT3 mutations in the hyper-IgE syndrome.
BACKGROUND
The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found.


METHODS
We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced.


RESULTS
We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-gamma, had higher tumor necrosis factor alpha levels than did identically treated cells from unaffected persons (P=0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P=0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains.


CONCLUSIONS
Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
Holland
Steven M
SM
National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. smh@nih.gov
DeLeo
Frank R
FR
Elloumi
Houda Z
HZ
Hsu
Amy P
AP
Uzel
Gulbu
G
Brodsky
Nina
N
Freeman
Alexandra F
AF
Demidowich
Andrew
A
Davis
Joie
J
Turner
Maria L
ML
Anderson
Victoria L
VL
Darnell
Dirk N
DN
Welch
Pamela A
PA
Kuhns
Douglas B
DB
Frucht
David M
DM
Malech
Harry L
HL
Gallin
John I
JI
Kobayashi
Scott D
SD
Whitney
Adeline R
AR
Voyich
Jovanka M
JM
Musser
James M
JM
Woellner
Cristina
C
Schäffer
Alejandro A
AA
Puck
Jennifer M
JM
Grimbacher
Bodo
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016207:Cytokines / Q000097:blood; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D007589:Job Syndrome / Q000235:genetics*; D007962:Leukocytes / Q000276:immunology; D008297:Male; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D050796:STAT3 Transcription Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
D016207:Cytokines; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human