Two patients with chronic mucocutaneous candidiasis caused by TRAF3IP2 deficiency

Shafer, Samantha; Yao, Yikun; Comrie, William A.; Cook, Sara; Zhang, Yu; Yeşil, Gözde; Karakoç-Aydıner, Elif; Barış, Safa; Çokuğraş, Haluk; Aydemir, Sezin; Kıykım, Ayça; Özen, Ahmet; Lenardo, Michael J.

doi:10.1016/j.jaci.2020.12.629

Cited by 12 publications

(14 citation statements)

References 16 publications

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“…This observation highlights the importance of functional assays, as the pattern of T‐cell differentiation is variable. Two previous reports, 12,16 as well as our case, revealed normal or slightly reduced IFN‐γ‐producing memory CD4 + cells whereas others observed reduced Th1 proportion 14 . Furthermore, and in contrast to previous cases, 14,16 levels of IL‐4‐producing Th2 cells were higher in our patient than those found in relatives, and healthy controls (Figure 5).…”

Section: Discussioncontrasting

confidence: 74%

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Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant

Lobo

Lei

Pelham

et al. 2021

Pediatric Allergy Immunology

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Background: Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL-17A and IL-17F. About half of the cases carry STAT1 gain-of-function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL-17 receptor(R) signaling. We investigated a 10-year-old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2. Methods: By flow cytometry, STAT1 levels and phosphorylation (CD14+) as well as IL-17A, IL-22, IFNγ, and IL-4 production (memory CD4 + T cells) were determined. ACT1 expression and binding to IL-17RA were assessed by Western blot and coimmunoprecipitation in HEK-293T cells transfected with plasmids encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We evaluated IL-17A responses by measuring luciferase induction under a NF-κB-driven reporter system in HEK-293T cells and Groα secretion in fibroblasts. Results: A STAT1 variant (c.1363G>A/p.V455I) was identified by next-generation sequencing and classified as likely non-pathogenic as functional testing revealed normal STAT1 expression and phosphorylation upon IFNγ. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant alleles resulted in impaired NF-κB activation. Patient's fibroblasts displayed abolished GROα secretion upon IL-17A stimulation. Finally, ex vivo CD4 + T cells showed increased IL-17A, IL-22, and IL-4 and normal low IFNγ expression upon stimulation. Conclusion:We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC and provide a review of the current literature.

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Section: Discussioncontrasting

confidence: 74%

“…Clinical and laboratory findings, and management of all eleven previously reported patients with AR ACT1 deficiency, including our report, are summarized in Figure 6 and, in more detail, inTable 12–16 . Of note, detailed information was not available for all patients.…”

Section: Discussionmentioning

confidence: 95%

Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant

Lobo

Lei

Pelham

et al. 2021

Pediatric Allergy Immunology

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show abstract

“…This observation highlights the importance of functional assays, as the pattern of T cell differentiation is variable. Two previous reports [12,16], as well as our case, revealed normal or slightly reduced IFN-γ-producing memory CD4 + cells whereas others observed reduced Th1 proportion [14]. Furthermore, and in contrast to previous cases [14,16], levels of IL-4-producing Th2 cells were higher in our patient than those found in relatives, and healthy controls (Figure 5) .…”

Section: Discussioncontrasting

confidence: 62%

“…Clinical and laboratory findings, and management of all eleven previously reported patients with AR ACT1 deficiency, including our report, are summarized in Figure 6 and, in more detail, insupplementary Table 3 [12][13][14][15][16]. Of note, detailed information was not available for all patients.…”

Section: Discussionmentioning

confidence: 95%

“…In contrast, patients displayed enhanced proportions of Th17 cells, as measured ex vivo upon PMA/ionomycin stimulation [12]. More recently, eight additional patients with mutations of TRAF3IP2 have been described [13][14][15][16]. We present a 10-year-old girl with CMC due to AR ACT1 deficiency and review important clinical and laboratory characteristics of the so far published cases.…”

Section: Introductionmentioning

confidence: 90%

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TRAF3IP2 variants in a child with chronic mucocutaneous candidiasis- keeping an open mind!

Lobo¹,

Lei²,

Pelham³

et al. 2021

Preprint

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Background: Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL-17A and IL-17F. About half of the cases carry STAT1 gain-of-function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL-17-receptor(R) -signaling. We investigated a 10-year-old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2. Methods: By flow cytometry STAT1 levels and phosphorylation (CD14+) as well as IL-17A-, IL-22-, IFN-γ- and IL-4-production (memory CD4+ T cells) were determined. ACT1 expression and binding to IL-17RA by western blot and co-immunoprecipitation in HEK-293T cells transfected with plasmids encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We evaluated IL-17A response using an NF-κB-driven luciferase reporter system in HEK-293T cells, and by measuring GRO-α secretion by fibroblasts. Results: A likely non-pathogenic STAT1 variant (c.1363G>A/p.V455I) was identified by next generation sequencing., STAT1 expression and phosphorylation upon IFN- were normal. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant alleles resulted in an impaired NF-κB-activation. Patient’s fibroblasts displayed abolished GRO-α secretion upon IL-17A. Finally, ex vivo CD4+ T cells showed increased IL-17A, IL-22, and IL-4, and normal-low IFN-γ expression upon stimulation. Conclusion: We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC, and provide a review of the current literature.

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A Novel TRAF3IP2 Mutation Causing Chronic Mucocutaneous Candidiasis

et al. 2021

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Two patients with chronic mucocutaneous candidiasis caused by TRAF3IP2 deficiency

Cited by 12 publications

References 16 publications

Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant

Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant

TRAF3IP2 variants in a child with chronic mucocutaneous candidiasis- keeping an open mind!

A Novel TRAF3IP2 Mutation Causing Chronic Mucocutaneous Candidiasis

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