Limits...
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.

Show MeSH

Related in: MedlinePlus

Ex vivo development of IL-17-producing and IL-22-producing T cells in P8 with the c.1154C>T STAT1 mutation. Percentages of CD3/IL-17+ (A), CD4/IL-17+ (B) and CD4/IL-22+ (C) cells, as determined by flow cytometry after incubation for 6 h with phorbol 12-myristate 13-acetate and ionomycin. At least three independent experiments were carried out in each case. C, control; P, patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3756505&req=5

JMEDGENET2013101570F4: Ex vivo development of IL-17-producing and IL-22-producing T cells in P8 with the c.1154C>T STAT1 mutation. Percentages of CD3/IL-17+ (A), CD4/IL-17+ (B) and CD4/IL-22+ (C) cells, as determined by flow cytometry after incubation for 6 h with phorbol 12-myristate 13-acetate and ionomycin. At least three independent experiments were carried out in each case. C, control; P, patient.

Mentions: PBMCs were isolated and treated with IL-17-inducing cytokines as described above. Flow cytometry was used to determine the percentages of CD3 T cells and CD4 T cells-producing cytoplasmic IL-17 or IL-22 (figure 4). Before marker analysis, the cells were treated with PMA and IMC for 6 h. Consistent with the cytokine-release data, the patient with the T385M STAT1 allele displayed impaired development of IL-17-producing and IL-22-producing T cells (figure 4A–C). Similar results were obtained for the cells of one of the patients (P4) with the heterozygous R274W allele (figure 4A–C).


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)

Ex vivo development of IL-17-producing and IL-22-producing T cells in P8 with the c.1154C>T STAT1 mutation. Percentages of CD3/IL-17+ (A), CD4/IL-17+ (B) and CD4/IL-22+ (C) cells, as determined by flow cytometry after incubation for 6 h with phorbol 12-myristate 13-acetate and ionomycin. At least three independent experiments were carried out in each case. C, control; P, patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

JMEDGENET2013101570F4: Ex vivo development of IL-17-producing and IL-22-producing T cells in P8 with the c.1154C>T STAT1 mutation. Percentages of CD3/IL-17+ (A), CD4/IL-17+ (B) and CD4/IL-22+ (C) cells, as determined by flow cytometry after incubation for 6 h with phorbol 12-myristate 13-acetate and ionomycin. At least three independent experiments were carried out in each case. C, control; P, patient.
Mentions: PBMCs were isolated and treated with IL-17-inducing cytokines as described above. Flow cytometry was used to determine the percentages of CD3 T cells and CD4 T cells-producing cytoplasmic IL-17 or IL-22 (figure 4). Before marker analysis, the cells were treated with PMA and IMC for 6 h. Consistent with the cytokine-release data, the patient with the T385M STAT1 allele displayed impaired development of IL-17-producing and IL-22-producing T cells (figure 4A–C). Similar results were obtained for the cells of one of the patients (P4) with the heterozygous R274W allele (figure 4A–C).

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