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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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Secretion of cytokines by blood mononuclear cells. (A) IFN-γ, IL-1β and IL-6 secretion by mononuclear blood cells (5×105) from P8 (see table 1) and unrelated healthy controls, as measured by enzyme-linked immunosorbent assays (ELISA), after stimulation with heat-killed C albicans (105) for 48 h. (B) Secretion of IL-17A and IL-22 by blood mononuclear cells (5×105) from P8 and unrelated healthy controls, as measured by ELISA, after stimulation with heat-killed Candida (105) for 48 h. (C) Cells from the patient and controls secreted similar amounts of IFN-γ, whereas (D) the patient's cells secreted much smaller amounts of both IL-17A and IL-22 than control cells. The data shown are representative of two experiments performed in triplicate. C, control; NS, non-stimulated; P, patient.
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JMEDGENET2013101570F3: Secretion of cytokines by blood mononuclear cells. (A) IFN-γ, IL-1β and IL-6 secretion by mononuclear blood cells (5×105) from P8 (see table 1) and unrelated healthy controls, as measured by enzyme-linked immunosorbent assays (ELISA), after stimulation with heat-killed C albicans (105) for 48 h. (B) Secretion of IL-17A and IL-22 by blood mononuclear cells (5×105) from P8 and unrelated healthy controls, as measured by ELISA, after stimulation with heat-killed Candida (105) for 48 h. (C) Cells from the patient and controls secreted similar amounts of IFN-γ, whereas (D) the patient's cells secreted much smaller amounts of both IL-17A and IL-22 than control cells. The data shown are representative of two experiments performed in triplicate. C, control; NS, non-stimulated; P, patient.

Mentions: We measured the release of various inflammatory cytokines by freshly isolated PBMCs after 48 h of stimulation with heat-killed Candida. Similar amounts of IFN-γ, IL-1β and IL-6 were released by the cells of P8 (T385M) and control cells (figure 3A). By contrast, PBMCs from P8 released negligible amounts of IL-17A and IL-22, much smaller than those released by Candida-exposed cells from healthy controls (figure 3B). Similar data were obtained with cells from P4 and P5 carrying the R274W allele (figure 3C,D). These data suggest a normal ‘Th1-type’ reaction, and normal IL-1β and IL-6 release in response to stimulation with C albicans, but an impaired ‘Th-17-type’ response to this fungus in patients with CMCD-associated mutations.


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)

Secretion of cytokines by blood mononuclear cells. (A) IFN-γ, IL-1β and IL-6 secretion by mononuclear blood cells (5×105) from P8 (see table 1) and unrelated healthy controls, as measured by enzyme-linked immunosorbent assays (ELISA), after stimulation with heat-killed C albicans (105) for 48 h. (B) Secretion of IL-17A and IL-22 by blood mononuclear cells (5×105) from P8 and unrelated healthy controls, as measured by ELISA, after stimulation with heat-killed Candida (105) for 48 h. (C) Cells from the patient and controls secreted similar amounts of IFN-γ, whereas (D) the patient's cells secreted much smaller amounts of both IL-17A and IL-22 than control cells. The data shown are representative of two experiments performed in triplicate. 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

JMEDGENET2013101570F3: Secretion of cytokines by blood mononuclear cells. (A) IFN-γ, IL-1β and IL-6 secretion by mononuclear blood cells (5×105) from P8 (see table 1) and unrelated healthy controls, as measured by enzyme-linked immunosorbent assays (ELISA), after stimulation with heat-killed C albicans (105) for 48 h. (B) Secretion of IL-17A and IL-22 by blood mononuclear cells (5×105) from P8 and unrelated healthy controls, as measured by ELISA, after stimulation with heat-killed Candida (105) for 48 h. (C) Cells from the patient and controls secreted similar amounts of IFN-γ, whereas (D) the patient's cells secreted much smaller amounts of both IL-17A and IL-22 than control cells. The data shown are representative of two experiments performed in triplicate. C, control; NS, non-stimulated; P, patient.
Mentions: We measured the release of various inflammatory cytokines by freshly isolated PBMCs after 48 h of stimulation with heat-killed Candida. Similar amounts of IFN-γ, IL-1β and IL-6 were released by the cells of P8 (T385M) and control cells (figure 3A). By contrast, PBMCs from P8 released negligible amounts of IL-17A and IL-22, much smaller than those released by Candida-exposed cells from healthy controls (figure 3B). Similar data were obtained with cells from P4 and P5 carrying the R274W allele (figure 3C,D). These data suggest a normal ‘Th1-type’ reaction, and normal IL-1β and IL-6 release in response to stimulation with C albicans, but an impaired ‘Th-17-type’ response to this fungus in patients with CMCD-associated mutations.

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