Novel bi‐allelic splice mutations in <i><scp>CARD</scp>9</i> causing adult‐onset <i>Candida</i> endophthalmitis

Gavino, Christina; Mellinghoff, Sibylle C.; Cornely, Oliver A.; Landekic, Marija; Le, Catherine; Langelier, Mélanie; Golizeh, Makan; Proske, Susanna; Vinh, Donald C.

doi:10.1111/myc.12701

Cited by 22 publications

(21 citation statements)

References 22 publications

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“…To analyze the role of CARD9 deficiency in fungal infection, we reviewed the literature and identified 60 cases until 2018. The total number of patients with severe fungal infection related to CARD9 deficiency has been summarized in Tables 1A , B ( Boudghène-Stambouli and Mérad-Boudia, 1989 , 1991 , 1998 ; Pruszkowski et al, 1995 ; Glocker et al, 2009 ; Drewniak et al, 2013 ; Gavino et al, 2014 ; Wang et al, 2014 ; Drummond et al, 2015 ; Grumach et al, 2015 ; Herbst et al, 2015 ; Jachiet et al, 2015 ; Lanternier et al, 2015a , b ; Alves de Medeiros et al, 2016 ; Gavino et al, 2016 ; Jones et al, 2016 ; Rieber et al, 2016 ; Yan et al, 2016 ; Boudghene-Stambouli et al, 2017 ; Gavino et al, 2018 ; Sari et al, 2018 ; Vaezi et al, 2018 ; Wang et al, 2018a , b ). The age at the time of diagnosis ranged from 4 to 91 years (mean 34.3 ± 17.9 years).…”

Section: Resultsmentioning

confidence: 99%

Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections

et al. 2018

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Autosomal recessive deficiency in the caspase recruitment domain containing protein 9 (CARD9) results in susceptibility to fungal infections. In the last decade, infections associated with CARD9 deficiency are more reported due to the advent of genome sequencing. The aim of this study was to evaluate the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency. We identified 60 patients with 24 mutations and different fungal infections. The presence of the homozygous (HMZ) p.Q295X (c.883C > T) and HMZ p.Q289X (c.865C > T) mutations were associated with an elevated risk of candidiasis (OR: 1.6; 95% CI: 1.18–2.15; p = 0.004) and dermatophytosis (OR: 1.85; 95% CI: 1.47–2.37; p < 0.001), respectively. The geographical distribution differed, showing that the main mutations in African patients were different Asian patients; HMZ p.Q289X (c.865C > T) and HMZ p.Q295X (c.865C > T) accounted for 75% and 37.9% of the African and Asian cases, respectively. The spectrum of CARD9 mutations in Asian patients was higher than in African. Asia is the most populous continent in the world and may have a greater genetic burden resulting in more patients with severe fungal infections. The presence of a high diversity of mutations revealing 24 distinct variations among 60 patients emphasize that the unique genetic alteration in CARD9 gene may be associated with certain geographical areas.

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Section: Resultsmentioning

confidence: 99%

Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections

et al. 2018

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“…The mutations identified were located in the 5’ UTR, CARD, or CCD regions (Figure 1). Missense ( n=11 ) [2–4,6–8,10,16–18,22], nonsense ( n=4 ) [1–3,5,8,9,11,14,15,20,21] and synonymous ( n=1 ) [18] mutations, small deletions ( n=3, 2 in-frame and 1 frameshift) [19,22], small insertions ( n=2, frameshift) [14,15,23] and a single-nucleotide substitution in the 5’ UTR region ( n=1 ) [6] were identified (Figure 1). Six of the mutations were recurrent, suggesting a founder effect.…”

Section: Human Card9 Mutationsmentioning

confidence: 99%

“…However, the second causal hit has not been identified in these patients, and may be an intronic mutation creating a splicing site. cDNA sequencing showed that c.184G>A (G62fs*) and c.288C>T (G96del36) created novel splice donor sites due to a 4 bp frameshift deletion and an in-frame deletion of 36 bp, respectively [19]. Both the c.184G>A and c.288C>T mRNAs were detected in LCLs.…”

Section: Experimental Analysis Of Card9 Mrnasmentioning

confidence: 99%

“…The impact of biallelic CARD9 mutations on protein production was assessed by western blotting and/or flow cytometry, with monoclonal (mAb) or polyclonal (pAb) anti-CARD9 antibodies (Table 3) [1–3,5–8,14–17,19,22]. Endogenous CARD9 expression was assessed in the PMBCs, neutrophils, MDMs, and/or MDDCs of the patients.…”

Section: Card9 Protein Production In the Patients’ Cellsmentioning

confidence: 99%

“…Support for this hypothesis was provided by the description of 14 additional patients (from 13 families) with the same clinical presentation [3,5–7,9–11,16,17]. However, although the CNS remains the main target organ of Candida infection in CARD9-deficient patients, Candida infections of other organs (eye: endophthalmitis, colon: colitis, bones: osteomyelitis) have been reported in seven patients (from seven families) [3,6–8,18,19]. Since the first description of CARD9 deficiency, the spectrum of invasive fungal diseases (IFD) in CARD9-deficient patients has progressively expanded, with the description of patients with extensive/deep dermatophytosis ( n=21 , from 12 families) [2,4,10,20,21], subcutaneous and invasive phaeohyphomycosis ( n=10 , from 10 families) [14,15,19,22,23], or extrapulmonary invasive aspergillosis (IA) ( n=2 , from 2 families) [8].…”

Section: Introductionmentioning

confidence: 99%

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Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults

2018

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• Inherited CARD9 deficiency (OMIM #212050) is an AR PID due to mutations that may be present in a homozygous or compound heterozygous state. • CARD9 is expressed principally in myeloid cells and transduces signals downstream from CLR activation by fungal ligands. • Endogenous mutant CARD9 levels differ between alleles (from full-length normal protein to an absence of normal protein). • The functional impacts of CARD9 mutations involve impaired cytokine production in response to fungal ligands, impaired neutrophil killing and/or recruitment to infection sites, and defects of Th17 immunity. • The key clinical manifestations in patients are fungal infections, including CMC, invasive (in the CNS in particular) Candida infections, extensive/deep dermatophytosis, subcutaneous and invasive phaeohyphomycosis, and extrapulmonary aspergillosis. • The clinical penetrance of CARD9 deficiency is complete, but penetrance is incomplete for each of the fungi concerned. • Age at onset is highly heterogeneous, ranging from childhood to adulthood for the same fungal disease. • All patients with unexplained IFD should be tested for CARD9 mutations. Familial screening and genetic counseling should be proposed. • The treatment of patients with CARD9 mutations is empirical and based on antifungal therapies and the surgical removal of fungal masses. Patients with persistent/relapsing Candida infections of the CNS could be considered for adjuvant GM-CSF/G-CSF therapy. The potential value of HSCT for CARD9-deficient patients remains unclear.

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Human inborn errors of immunity underlying superficial or invasive candidiasis

Puel

2020

Hum Genet

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Novel bi‐allelic splice mutations in CARD9 causing adult‐onset Candida endophthalmitis

Abstract: Summary K E Y W O R D Sbi-allelic, candidiasis, CARD9, splicing

Cited by 22 publications

References 22 publications

Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections

Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections

Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults

Human inborn errors of immunity underlying superficial or invasive candidiasis

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