A novel immunodeficiency disorder characterized by genetic amplification of interleukin 25

Green, Michael R.; Camilleri, Emily T.; Gandhi, Maher K.; Peake, Jane; Griffiths, Lyn R.

doi:10.1038/gene.2011.50

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…Such LCSH areas are likely to reflect the origin of recessive diseases, such as imprinting disorders, triploidy and duplications in which the pathogenic mutations are located (4). Although not observed in this study, 22q11 microdeletion syndrome (4) and IL-25 hyperdiploidy can be discovered by CNV analysis (15). SNVs related to inflammatory and autoimmune complications in common variable immunodeficiency (CVID) were reported (16).…”

Section: Discussionmentioning

confidence: 60%

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

et al. 2020

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Section: Discussionmentioning

confidence: 60%

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

et al. 2020

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“…We previously investigated a functional molecular cause for this undiagnosed immunodeficiency through whole genome arrays. Briefly, analysis of Affymetrix 250K SNP microarray data of the case and a matched healthy control subject via a copy number analysis tool identified hyperploidy of a region centromeric to chromosome 14q11.2, mapped over the interleukin 25 ( IL25 ) gene ( 10 ). IL-25 (a member of the IL-17 family of cytokines) induction in mice has been previously associated with a T-helper (Th) 2-like pathological immune response ( 11 ) and shown to regulate the development of autoimmune inflammation mediated by IL-17-producing cells ( 12 , 13 ) and was deemed a plausible candidate for further analyses.…”

Section: Introductionmentioning

confidence: 99%

“…Green et al ( 10 ) paired genetic analysis with transcriptional profiling and found a large number of genes associated with Th1/Th2 profiles to be differentially expressed in peripheral blood lymphocytes of the proband, indicative of a Th2 bias confirmed by flow cytometric analysis. T-cells from the proband and control subject were cultured and activated in vitro with qPCR analysis demonstrating higher IL25 expression in the proband when compared to the control.…”

Section: Introductionmentioning

confidence: 99%

Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case

et al. 2018

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BackgroundWe investigated the molecular etiology of a young male proband with confirmed immunodeficiency of unknown cause, presenting with recurrent bacterial and Varicella zoster viral infections in childhood and persistent lymphopenia into early adulthood.AimTo identify causative functional genetic variants related to an undiagnosed primary immunodeficiency.MethodWhole genome microarray copy number variant (CNV) analysis was performed on the proband followed by whole exome sequencing (WES) and trio analysis of the proband and family members. A >4 kbp deletion identified by repeated CNV analysis of exome sequencing data along with three damaging missense single nucleotide variants were validated by Sanger sequencing in all family members. Confirmation of the causative role of the candidate gene was performed by qPCR and Western Blot analyses on the proband, family members and a healthy control.ResultsCNV identified our previously reported interleukin 25 amplification in the proband; however, the variant was not validated to be a candidate gene for immunodeficiency. WES trio analysis, data filtering and in silico prediction identified a novel, damaging (SIFT: 0; Polyphen 1; Grantham score: 101) and disease-causing (MutationTaster) single base mutation in the X chromosome (c.511C > T p.Arg171Trp) MSN gene not identified in the UCSC Genome Browser database. The mutation was validated by Sanger sequencing, confirming the proband was hemizygous X-linked recessive (–/T) at this locus and inherited the affected T allele from his non-symptomatic carrier mother (C/T), with other family members (father, sister) confirmed to be wild type (C/C). Western Blot analysis demonstrated an absence of moesin protein in lymphocytes derived from the proband, compared with normal expression in lymphocytes derived from the healthy control, father and mother. qPCR identified significantly lower MSN mRNA transcript expression in the proband compared to an age- and sex-matched healthy control subject in whole blood (p = 0.02), and lymphocytes (p = 0.01). These results confirmed moesin deficiency in the proband, directly causative of his immunodeficient phenotype.ConclusionThese findings confirm X-linked moesin-associated immunodeficiency in a proband previously undiagnosed up to 24 years of age. This study also highlights the utility of WES for the diagnosis of rare or novel forms of primary immunodeficiency disease.

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“…IL17RB encodes a cytokine receptor that specifically binds to IL‐25 (IL‐17E) and IL‐17B, in which IL‐17B is thought to be an antagonist of IL‐25 binding ( 32 ). IL‐25 induces Th2‐type cytokine production in IL17RB‐positive cells ( 32 ), and in a case report, genetic amplification of IL‐25 led to an overactive Th2 response with a phenotype of recurrent varicella ( 42 ). In this analysis, the IL17RB locus variant was also associated with lowered proportions of Th17/Treg cells in healthy Japanese individuals.…”

Section: Discussionmentioning

confidence: 99%

Contribution of a European‐Prevalent Variant near CD83 and an East Asian–Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome‐Wide Association Study Meta‐Analyses

Bing

Zhou

Chen

et al. 2021

Arthritis & Rheumatology

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Objective Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta‐analysis of genome‐wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. Methods In an ethnicity/indication‐specific, trans‐ethnic, trans‐population meta‐analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long‐term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. Results In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10−8), including a single‐nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans‐ethnic, trans‐population meta‐analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta‐analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta‐analysis hazard ratio 3.6 [95% confidence interval 2.40–5.44], P = 7.6 × 10−10; frequency of risk allele ~12% in East Asian subjects versus <0.2% in European subjects). Conclusion Genetic analysis of tofacitinib‐treated subjects with RA or PsO identified multiple loci associated with increased HZ risk. Prevalent variants near the immune‐relevant genes CD83 and IL17RB in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib‐treated subjects.

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A novel immunodeficiency disorder characterized by genetic amplification of interleukin 25

Cited by 5 publications

References 22 publications

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

Rapid Low-Cost Microarray-Based Genotyping for Genetic Screening in Primary Immunodeficiency

Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case

Contribution of a European‐Prevalent Variant near CD83 and an East Asian–Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome‐Wide Association Study Meta‐Analyses

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