Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups.
We performed clinical, immunological and genetic studies of 12 hyper-IgE syndrome (HIES) patients from 4 Hungarian, 2 Lebanese, one Russian, one Polish, and one Swedish families with autosomal dominant (AD) or sporadic forms of the disease to reveal cross-ethnicity of recurrent and novel mutations in the signal transducer and activator of transcription-3 gene (STAT3). Four patients from 3 Hungarian families, and one Russian, and one Swedish patient carried the heterozygous R382W germline mutation at the DNA-binding site of STAT3. The recurrent V637M mutation affecting the SRC homology 2 (SH2) domain was detected in one Lebanese and one Polish family, and the V463del deletion located in the DNA-binding domain was unveiled in another Lebanese family. A novel H332Y mutation affecting the DNA-binding site of STAT3 in three Hungarian patients from a Gypsy family was also found. The segregation of this mutation with HIES, restriction fragment length polymorphism analysis of STAT3 from patients and controls and the negligible production upon IL-6 stimulation of monocyte chemotactic protein-1 by the patient's blood mononuclear cells suggested that the H332Y mutation was disease-causing. These data suggest, that dominant negative mutations of the DNA-binding and SH2 domains of STAT3 cause AD and sporadic cases of HIES in different ethnic groups with R382W as the predominant mutation found in 5 of the 9 families. Functional and genetic data support that the novel H332Y mutation may result in the loss of function of STAT3 and leads to the HIES phenotype.
Jiao
Hong
H
Department of Biosciences and Nutrition, Clinical Research Center, Karolinska Institute, Stockholm, Sweden.
Tóth
Beáta
B
Erdos
Melinda
M
Fransson
Ingegerd
I
Rákóczi
Eva
E
Balogh
István
I
Magyarics
Zoltán
Z
Dérfalvi
Beáta
B
Csorba
Gabriella
G
Szaflarska
Anna
A
Megarbane
Andre
A
Akatcherian
Carlo
C
Dbaibo
Ghassan
G
Rajnavölgyi
Eva
E
Hammarström
Lennart
L
Kere
Juha
J
Lefranc
Gérard
G
Maródi
László
L
D000328:Adult; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000378:metabolism; D003710:Demography; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D006801:Humans; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology*; D008297:Male; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015183:Restriction Mapping; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004247:DNA