Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups

Jiao, Hong; Töth, Beáta; Erdős, Melinda; Fransson, Ingegerd; Rákóczi, Éva; Balogh, István; Magyarics, Zoltán; Dérfalvi, Beáta; Csorba, Gabriella; Szaflarska, Anna; Mégarbané, André; Akatcherian, C; Dbaibo, Ghassan; Rajnavölgyi, Éva; Hammarström, Lennart; Kere, Juha; Lefranc, Gérard; Maródi, László

doi:10.1016/j.molimm.2008.07.001

Cited by 84 publications

(63 citation statements)

References 17 publications

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“…Infection may not be the only sign for the clinical and immunological diagnosis of PIDs and, indeed, it may not even be the most useful sign in some PIDs. Furthermore, contrary to the traditional view that PID patients have recurrent, severe infections caused by various pathogens, we have found that some PIDs predispose patients to infection with only one or a few pathogens [17][18][19][20][21].…”

Section: Pid Registry and Non-immune Pid Phenotypescontrasting

confidence: 92%

Editorial Affiliation of the J Project Group to the Central European Journal of Immunology

Maródi¹

2012

cejoi

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Section: Pid Registry and Non-immune Pid Phenotypescontrasting

confidence: 92%

Editorial Affiliation of the J Project Group to the Central European Journal of Immunology

Maródi¹

2012

cejoi

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“…We chose a common mutation identified in multiple patient cohorts, namely deletion of V463 in STAT3ʹs DNA-binding domain, 2,3,26 and used BAC recombineering 27 to generate transgenic mice, which expressed this mutant allele (denoted mut-Stat3) ( Figure 1A). From 6 transgenic lines generated, 1 was used for all subsequent experiments as it expressed 2 copies of the transgene (Figure 1B), providing the appropriate ratio of WT to mutant alleles seen in HIES patients.…”

Section: Mut-stat3 Mice Recapitulate Biochemical and Functional Featumentioning

confidence: 99%

A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3

Steward-Tharp

Laurence

Kanno

et al. 2014

Blood

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• Mice that express a mutation in STAT3 phenocopy patients with HIES.• Bone marrow transplantation does not fully correct the susceptibility of these animals to bacterial infection.Mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in nonhematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and nonhematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild-type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of

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“…Similar dominant-negative activities caused by missense mutations in DNA-binding domains of transcription factors have been shown to result in disease. Such mutations have been described in PITX1, associated with autosomal dominant club foot, 36 in STAT3, associated with hyper-IgE syndrome, 37 in AIRE, associated with autosomal dominant autoimmune thyroiditis, 38 and in somatic mutations of IRF5 in chronic lymphocytic leukemia and adult T-cell leukemia/lymphoma. 39 There is also precedent for different mutations within the same gene causing variable disease phenotypes; in connective tissue disorders, such as osteogenesis imperfecta, missense mutations are associated with a more severe phenotype than nonsense mutations, 40 although the effect seen here is not as substantive.…”

Section: Mutations In Tcf4mentioning

confidence: 99%

Genotype–phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations

Rosenfeld

Leppig

Ballif

et al. 2009

Genetics in Medicine

101

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Purpose: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splicesite mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the PittHopkins syndrome phenotype is independent of mutation or deletion type. Methods: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. Results: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with PittHopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. Conclusions: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations. itt-Hopkins syndrome (PTHS, OMIM 610954) was first described in 1978 1 in two individuals and is characterized by specific dysmorphic features (deep-set eyes, broad-beaked nose, wide mouth with bow-shaped upper lip, and widely spaced teeth), childhood-onset hyperventilation episodes, childhood-onset seizures, microcephaly, and severe psychomotor retardation with a happy disposition. It is an autosomal dominant condition caused by haploinsufficiency for TCF4 (transcription factor 4, OMIM 602272) on 18q21.2. [2][3][4] The etiology of PTHS was determined when two groups concurrently screened individuals with PTHS for chromosomal deletions using microarray technology, one with arraybased comparative genomic hybridization (aCGH) 5 and the other with single-nucleotide polymorphism-based molecular karyotyping. 3 Each group described a patient with a de novo deletion involving this gene. Further screening of individuals with PTHS or phenotypic overlap with PTHS found individuals with de novo missense and nonsense mutations in TCF4. 3,5 Subsequently, more individuals have been published with disruptions, deletions, and mutations in TCF4, most with typical PTHS features. 4,6 -10 TCF4 is a transcription factor that belongs to the class I basic helix-loop-helix (bHLH) protein family, also known as the "E-protein" family. These proteins form homo-and heterodimers with other heli...

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Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups

Cited by 84 publications

References 17 publications

Editorial Affiliation of the J Project Group to the Central European Journal of Immunology

Editorial Affiliation of the J Project Group to the Central European Journal of Immunology

A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3

Genotype–phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations

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