Autosomal Dominant Cases of Chronic Mucocutaneous Candidiasis Segregates with Mutations of Signal Transducer and Activator of Transcription 1, But Not of Toll-Like Receptor 3

Rushood, Maysoun Al; McCusker, Christine; Mazer, Bruce; Alizadehfar, Reza; Grimbacher, Bodo; Depner, Mark; Ben‐Shoshan, Moshe

doi:10.1016/j.jpeds.2013.02.040

Cited by 22 publications

(12 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…and A.P., unpublished data). 20,21,23,30,33,35,43,44,[46][47][48] Blood leukocyte subsets were analyzed in 232 patients (Table 1) 60 were observed in 82% of 49 patients and 40% of 10 patients tested, respectively. Further details regarding genetic and immunological features are described in the supplemental Appendix.…”

Section: Genetic and Immunological Featuresmentioning

confidence: 99%

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Toubiana

Okada

Hiller

et al. 2016

Blood

Self Cite

489

649

View full text Add to dashboard Cite

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-GuÃ©rin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis

show abstract

Section: Genetic and Immunological Featuresmentioning

confidence: 99%

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Toubiana

Okada

Hiller

et al. 2016

Blood

Self Cite

489

649

View full text Add to dashboard Cite

show abstract

“…AR IL-17RA deficiency, AR ACT1 deficiency, and AD IL-17F deficiency were described, each in a single kindred ( Puel et al, 2011 ; Boisson et al, 2013 ). A fourth genetic etiology of CMCD, which currently appears to be the most frequent, has also been reported: heterozygous gain-of-function (GOF) mutations of STAT1 impairing the development of IL-17–producing T cells ( Liu et al, 2011 ; Smeekens et al, 2011 ; van de Veerdonk et al, 2011 ; Hori et al, 2012 ; Takezaki et al, 2012 ; Tóth et al, 2012 ; Al Rushood et al, 2013 ; Aldave et al, 2013 ; Romberg et al, 2013 ; Sampaio et al, 2013 ; Soltész et al, 2013 ; Uzel et al, 2013 ; Wildbaum et al, 2013 ; Frans et al, 2014 ; Kilic et al, 2014 ; Lee et al, 2014 ; Mekki et al, 2014 ; Mizoguchi et al, 2014 ; Sharfe et al, 2014 ; Yamazaki et al, 2014 ). We studied three unrelated patients with CMCD without mutations of IL17F , IL17RA , ACT1 , or STAT1 .…”

mentioning

confidence: 99%

Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis

Ling

Cypowyj

Aytekin

et al. 2015

Journal of Experimental Medicine

167

138

View full text Add to dashboard Cite

show abstract

“…In 2011, heterozygous STAT1 mutations were reported as a cause of CMCD (3,4), and since then, 30 aa changes have been reported: 21 in the coiled-coil domain (CCD) and 9 in the DNA-binding domain (DBD) (see Fig. 1A) (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Accumulated data indicated these mutations account for around half of CMCD patients and were associated with gain of STAT1 function due to impaired dephosphorylation of STAT1 (4,13).…”

mentioning

confidence: 99%

Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chronic Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of Anti–IL-17F Autoantibody

Yamazaki

Yamada

Kawai

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Heterozygous gain-of-function (GOF) mutations of STAT1 are responsible for chronic mucocutaneous candidiasis disease (CMCD), one of the primary immunodeficiency diseases characterized by susceptibility to mucocutaneous Candida infection. To date, 30 aa changes have been reported: 21 in the coiled-coil domain and 9 in the DNA-binding domain. In this study, we report two novel STAT1 GOF mutations of p.K278E in coiled-coil domain and p.G384D in DNA-binding domain in Japanese CMCD patients. Ectopic expression of these STAT1 mutants in HeLa cells was associated with increased phosphorylation of the mutant and the endogenous wild-type STAT1 due to impaired dephosphorylation, indicating heterodimers of the wild-type and mutant STAT1 cause impaired dephosphorylation, as did homodimers of the mutants. Because IL-17A production was not significantly reduced at least in one of the patients following PMA plus ionomycin stimulation, we further studied Th17-associated cytokines IL-17A, IL-17F, and IL-22 in response to more physiologically relevant stimulations. IL-17A and IL-22 production from PBMCs and CD4(+) cells was significantly reduced in four patients with STAT1 GOF mutations, including the previously reported R274Q in response to anti-CD3 plus anti-CD28 Abs or Candida stimulations. In contrast, IL-17F production was comparable to healthy controls in response to anti-CD3 plus anti-CD28 Abs stimulation. These results indicate impaired production of IL-17A and IL-22 rather than IL-17F was associated with the development of CMCD in these patients. Additionally, only the anti-IL-17F autoantibody was detected in sera from 11 of 17 patients with STAT1 GOF mutations, which may be useful as a marker for this disease.

show abstract

Autosomal Dominant Cases of Chronic Mucocutaneous Candidiasis Segregates with Mutations of Signal Transducer and Activator of Transcription 1, But Not of Toll-Like Receptor 3

Cited by 22 publications

References 13 publications

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis

Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chronic Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of Anti–IL-17F Autoantibody

Contact Info

Product

Resources

About