A novel IL2RG mutation presenting with atypical T−B+NK+ phenotype: Rapid elucidation of NK cell origin

Estévez, Orlando A.; Ortega, Consuelo; Fernández, Silvia Pérez; Aguado, Rocío; Rumbao, José; Pérez-Navero, Juan Luís; Santamarı́a, Manuel

doi:10.1002/pbc.24717

Cited by 10 publications

(7 citation statements)

References 4 publications

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“…Patients suffering from X-linked SCID but with T-B− phenotype have been described previously (28). Patients with documented IL2RG mutations but with T-B+NK+ phenotype were also described previously (50–52). Many possible mechanisms can lead to atypical SCID immunophenotypes, including concurrent mutations in other SCID genes, modifier gene(s), and mutations, that lead to sparing or disrupting developments of other lineages of lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

et al. 2017

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BackgroundSevere combined immunodeficiency (SCID) is fatal unless treated with hematopoietic stem cell transplant. Delay in diagnosis is common without newborn screening. Family history of infant death due to infection or known SCID (FH) has been associated with earlier diagnosis.ObjectiveThe aim of this study was to identify the clinical features that affect age at diagnosis (AD) and time to the diagnosis of SCID.MethodsFrom 2005 to 2016, 147 SCID patients were referred to the Asian Primary Immunodeficiency Network. Patients with genetic diagnosis, age at presentation (AP), and AD were selected for study.ResultsA total of 88 different SCID gene mutations were identified in 94 patients, including 49 IL2RG mutations, 12 RAG1 mutations, 8 RAG2 mutations, 7 JAK3 mutations, 4 DCLRE1C mutations, 4 IL7R mutations, 2 RFXANK mutations, and 2 ADA mutations. A total of 29 mutations were previously unreported. Eighty-three of the 94 patients fulfilled the selection criteria. Their median AD was 4 months, and the time to diagnosis was 2 months. The commonest SCID was X-linked (n = 57). A total of 29 patients had a positive FH. Candidiasis (n = 27) and bacillus Calmette–Guérin (BCG) vaccine infection (n = 19) were the commonest infections. The median age for candidiasis and BCG infection documented were 3 months and 4 months, respectively. The median absolute lymphocyte count (ALC) was 1.05 × 109/L with over 88% patients below 3 × 109/L. Positive FH was associated with earlier AP by 1 month (p = 0.002) and diagnosis by 2 months (p = 0.008), but not shorter time to diagnosis (p = 0.494). Candidiasis was associated with later AD by 2 months (p = 0.008) and longer time to diagnosis by 0.55 months (p = 0.003). BCG infections were not associated with age or time to diagnosis.ConclusionFH was useful to aid earlier diagnosis but was overlooked by clinicians and not by parents. Similarly, typical clinical features of SCID were not recognized by clinicians to shorten the time to diagnosis. We suggest that lymphocyte subset should be performed for any infant with one or more of the following four clinical features: FH, candidiasis, BCG infections, and ALC below 3 × 109/L.

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Section: Discussionmentioning

confidence: 99%

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

et al. 2017

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“…Several cases with rare hemizygous IL2RG mutations and milder phenotypes, like X-linked combined immunodeficiency (CID) or common variable immunodeficiency (CVID), have been reported [2,[10][11][12][13]. Caused by hypomorphic mutations, genetic reversions in the early progenitor cells, or maternal T or NK cell engraftment, these atypical or "leaky" phenotypes may display preserved and/or partially functional T and NK cell subsets [3,10,12,[14][15][16][17][18][19]. Typical and atypical X-SCID have overlapping clinical features such as recurrent bacterial and viral infections, often caused by opportunistic pathogens.…”

Section: Introductionmentioning

confidence: 99%

Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency

et al. 2020

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Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as proteinprotein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.

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“… 4 Although most of the known mutations result in a classical immunophenotype of T − B + NK − SCID, variants leading to a T − B + NK + SCID and T low B + NK + have been described. 5 , 6 Attenuated SCID phenotypes have also been observed as a result of splice-site mutations resulting in diminished expression of truncated γc protein or as a result of somatic reversion. 5 , 6 , 7 …”

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confidence: 99%

Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor γ (IL2RG) gene promoter

Chandra¹,

Zhang

Gilmour

et al. 2016

Journal of Allergy and Clinical Immunology

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A novel IL2RG mutation presenting with atypical T⁻B⁺NK⁺ phenotype: Rapid elucidation of NK cell origin

Cited by 10 publications

References 4 publications

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

Novel Hemizygous IL2RG p.(Pro58Ser) Mutation Impairs IL-2 Receptor Complex Expression on Lymphocytes Causing X-Linked Combined Immunodeficiency

Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor γ (IL2RG) gene promoter

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