Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency

Natarajan, Mukil; Hsu, Amy P.; Weinreich, Michael; Zhang, Yuan; Niemela, Julie E.; Butman, John A.; Pittaluga, Stefania; Sugui, Janyce A.; Collar, Amanda L.; Lim, Jean K.; Zangeneh, Tirdad T.; Carr, Tara F.; Oler, Andrew J.; Similuk, Morgan; Rosen, Lindsey B.; Desai, Jigar V.; Freeman, Alexandra F.; Holland, Steven M.; Kwon‐Chung, Kyung J.; Milner, Joshua D.; Lionakis, Michail S.

doi:10.1016/j.jaci.2018.05.009

Cited by 18 publications

(26 citation statements)

References 19 publications

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“…Recently, A. fumisynnematus was identified in a patient with underlying STAT3 haploinsufficiency caused by a novel STAT3 splice site mutation. The patient had elevated IgE, allergic rhinitis, eosinophilic esophagitis, and fatal IA due to this species [13].…”

Section: Human Pids Associated With Invasive Aspergillosismentioning

confidence: 99%

“…Aspergillus fumigatus is the primary cause of IA in individuals with PIDs, followed by A. nidulans, due to its propensity to cause infection in patients with CGD [5]. Other aspergilli also documented to infect PID patients include A. pseudoviridinutans [6], A. tanneri [7], A. udagawae [8], A. flavus [9], A. niger [10], A. calidoustus [11], A. quadrilineatus [12], A. fumisynnematus [13], and A. subramanianii . Without proper identification of the etiologic agents and adequate therapy, IA results in high mortality rates regardless of the species involved [14].…”

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confidence: 99%

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Emerging Aspergillus Species Almost Exclusively Associated With Primary Immunodeficiencies

Seyedmousavi

Lionakis

Parta

et al. 2018

Open Forum Infectious Diseases

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Invasive aspergillosis (IA) is the most serious mold infection encountered in patients with iatrogenic immunosuppression. IA is also a major cause of mortality and morbidity in individuals with primary immunodeficiency (PID). Although Aspergillus fumigatus is the most common etiologic agent of IA reported in PID patients, followed by A. nidulans, multiple poorly recognized Aspergillus species such as A. udagawae, A. quadrilineatus, A. pseudoviridinutans, A. tanneri, A. subramanianii, and A. fumisynnematus have been reported almost exclusively from patients with inborn defects in host antifungal defense pathways. Infection in PID patients exhibits patterns of disease progression distinct from those in iatrogenic immunosuppression. Specifically, the disease can be extrapulmonary and chronic with a tendency to disseminate in a contiguous manner across anatomical planes. It is also more refractory to standard antifungal therapy. This synopsis summarizes our understanding of emerging rare Aspergillus species that primarily affect patients with PIDs but not those with acquired immunodeficiencies.

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Section: Human Pids Associated With Invasive Aspergillosismentioning

confidence: 99%

mentioning

confidence: 99%

Emerging Aspergillus Species Almost Exclusively Associated With Primary Immunodeficiencies

Seyedmousavi

Lionakis

Parta

et al. 2018

Open Forum Infectious Diseases

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“…Almost all AD HIES-causing STAT3 mutations are in frame and located in specific domains of the protein, strongly suggesting that negative dominance is the general rule for the mechanism of action of these mutations. Frameshift mutations of STAT3 have recently been reported, and this discovery was interpreted as evidence that dominance might also operate by haploinsufficiency (29,31). Dominance effects based on negative dominance require the encoded mutant protein to inhibit the WT protein, by interfering with its function (90).…”

Section: Discussionmentioning

confidence: 99%

“…Remarkably, all of the mutations identified to date are in-frame mutations. However, potential exceptions to this apparent rule were recently reported, in the form of out-offrame mutations due to nonsense (S381*) (31) or frameshift variants (R13Vfs*23, F493Lfs*508, Y657*) (29). However, no causal link between these out-of-frame mutations and HIES was established, because dominance was not experimentally investi-gated at the cellular level.…”

Section: Significancementioning

confidence: 99%

“…Given that all of the other mutations identified were also in frame, by inference, these other STAT3 mutations have also been widely assumed to be DN (8,14). It has been suggested, but not proved, that the recently reported out-of-frame STAT3 mutations are dominant, and pathogenic via haploinsufficiency (31). Moreover, the production of in-frame mutant STAT3 proteins in heterozygous cells has not been documented, making it impossible to define a threshold level above which mutants exert DN effects.…”

Section: Significancementioning

confidence: 99%

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A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Khourieh

Rao

Habib

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

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Exome sequencing study in a clinical research setting finds general acceptance of study returning secondary genomic findings with little decisional conflict

Similuk

Yan

Setzer

et al. 2020

Journal of Genetic Counseling

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The return of individual genetic results from clinical research varies considerably by study (Wynn et al., 2015). This variability is partly dependent on study context, such as the relationship between investigator and participant, available resources, institutional norms, and investigator preference (Jarvik et al., 2014). For example, a genomic research study where physicians provide individual medical recommendations or administer treatment to participants has different ethical obligations than a research study doing genomic analysis on samples from de-identified biobank participants. One area without consensus is the return of secondary findings (SF) in a research setting (Wolf et al., 2015). Return of a selected consensus set of SF is recommended in the clinical setting by the American College of Medical Genetics and Genomics (ACMG) (Green et al., 2013;Kalia et al., 2017).One way to inform policy on the return of SF in the research setting is to conduct research on patient knowledge and preferences.In one study conducted at the National Institutes of Health (NIH) Clinical Center (CC), where the current study was also conducted,

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Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency

Cited by 18 publications

References 19 publications

Emerging Aspergillus Species Almost Exclusively Associated With Primary Immunodeficiencies

Emerging Aspergillus Species Almost Exclusively Associated With Primary Immunodeficiencies

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Exome sequencing study in a clinical research setting finds general acceptance of study returning secondary genomic findings with little decisional conflict

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