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New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe.

Soltész B, Tóth B, Shabashova N, Bondarenko A, Okada S, Cypowyj S, Abhyankar A, Csorba G, Taskó S, Sarkadi AK, Méhes L, Rozsíval P, Neumann D, Chernyshova L, Tulassay Z, Puel A, Casanova JL, Sediva A, Litzman J, Maródi L - J. Med. Genet. (2013)

Bottom Line: The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient.Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients.Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary, EU.

ABSTRACT

Background: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear.

Objective: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation.

Results: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented.

Conclusions: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.

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Related in: MedlinePlus

Concentrations of IL-17F in the supernatant of lymphocytes after 5 days of differentiation in vitro. Cells were treated with transforming growth factor-β1, IL-1β, IL-6, rhIL-21, rhIL-23 and IL-2, as described in ‘Patients and methods’ section. IL-17F levels were determined, by enzyme-linked immunosorbent assays, in the supernatant of cells from two healthy controls, patients P4 and P5 with the R274W allele, and a patient with hyper-IgE syndrome caused by a heterozygous dominant negative c.994C>T (H332Y) mutation of STAT3. C, control; NS, non-stimulated; P, patient.
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JMEDGENET2013101570F5: Concentrations of IL-17F in the supernatant of lymphocytes after 5 days of differentiation in vitro. Cells were treated with transforming growth factor-β1, IL-1β, IL-6, rhIL-21, rhIL-23 and IL-2, as described in ‘Patients and methods’ section. IL-17F levels were determined, by enzyme-linked immunosorbent assays, in the supernatant of cells from two healthy controls, patients P4 and P5 with the R274W allele, and a patient with hyper-IgE syndrome caused by a heterozygous dominant negative c.994C>T (H332Y) mutation of STAT3. C, control; NS, non-stimulated; P, patient.

Mentions: We also measured the release of IL-17F by PBMCs from P4 and P5 after the cytokine-induced in vitro differentiation of T cells into IL-17-producing lymphocytes. After 5 days of cytokine treatment, the cells were stimulated with PMA and IMC for 6 h and IL-17F concentrations were determined by enzyme-linked immunosorbent assays (ELISA) on the supernatants. Control experiments were performed with cells isolated from healthy individuals and with cells obtained from a patient with AD-HIES caused by a dominant negative mutation of STAT3 (figure 5). An impairment of IL-17F release by the cells of both CMCD patients bearing the R274W allele and by the cells of the patients with AD-HIES was observed.


New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe.

Soltész B, Tóth B, Shabashova N, Bondarenko A, Okada S, Cypowyj S, Abhyankar A, Csorba G, Taskó S, Sarkadi AK, Méhes L, Rozsíval P, Neumann D, Chernyshova L, Tulassay Z, Puel A, Casanova JL, Sediva A, Litzman J, Maródi L - J. Med. Genet. (2013)

Concentrations of IL-17F in the supernatant of lymphocytes after 5 days of differentiation in vitro. Cells were treated with transforming growth factor-β1, IL-1β, IL-6, rhIL-21, rhIL-23 and IL-2, as described in ‘Patients and methods’ section. IL-17F levels were determined, by enzyme-linked immunosorbent assays, in the supernatant of cells from two healthy controls, patients P4 and P5 with the R274W allele, and a patient with hyper-IgE syndrome caused by a heterozygous dominant negative c.994C>T (H332Y) mutation of STAT3. C, control; NS, non-stimulated; P, patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756505&req=5

JMEDGENET2013101570F5: Concentrations of IL-17F in the supernatant of lymphocytes after 5 days of differentiation in vitro. Cells were treated with transforming growth factor-β1, IL-1β, IL-6, rhIL-21, rhIL-23 and IL-2, as described in ‘Patients and methods’ section. IL-17F levels were determined, by enzyme-linked immunosorbent assays, in the supernatant of cells from two healthy controls, patients P4 and P5 with the R274W allele, and a patient with hyper-IgE syndrome caused by a heterozygous dominant negative c.994C>T (H332Y) mutation of STAT3. C, control; NS, non-stimulated; P, patient.
Mentions: We also measured the release of IL-17F by PBMCs from P4 and P5 after the cytokine-induced in vitro differentiation of T cells into IL-17-producing lymphocytes. After 5 days of cytokine treatment, the cells were stimulated with PMA and IMC for 6 h and IL-17F concentrations were determined by enzyme-linked immunosorbent assays (ELISA) on the supernatants. Control experiments were performed with cells isolated from healthy individuals and with cells obtained from a patient with AD-HIES caused by a dominant negative mutation of STAT3 (figure 5). An impairment of IL-17F release by the cells of both CMCD patients bearing the R274W allele and by the cells of the patients with AD-HIES was observed.

Bottom Line: The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient.Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients.Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary, EU.

ABSTRACT

Background: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear.

Objective: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation.

Results: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented.

Conclusions: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.

Show MeSH
Related in: MedlinePlus