title: Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups.
abstract: 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.
authors.affiliation: Department of Biosciences and Nutrition, Clinical Research Center, Karolinska Institute, Stockholm, Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.forename: Beáta
authors.initials: B
authors.lastname: Tóth
authors.forename: Melinda
authors.initials: M
authors.lastname: Erdos
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Fransson
authors.forename: Eva
authors.initials: E
authors.lastname: Rákóczi
authors.forename: István
authors.initials: I
authors.lastname: Balogh
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Magyarics
authors.forename: Beáta
authors.initials: B
authors.lastname: Dérfalvi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Csorba
authors.forename: Anna
authors.initials: A
authors.lastname: Szaflarska
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Carlo
authors.initials: C
authors.lastname: Akatcherian
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.forename: Eva
authors.initials: E
authors.lastname: Rajnavölgyi
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Gérard
authors.initials: G
authors.lastname: Lefranc
authors.forename: László
authors.initials: L
authors.lastname: Maródi
mesh_terms: 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*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004247:DNA