A novel intronic splice site deletion of the IL-2 receptor common gamma chain results in expression of a dysfunctional protein and T-cell-positive X-linked Severe combined immunodeficiency

2014 ◽  
Vol 42 (1) ◽  
pp. 11-14 ◽  
Author(s):  
P. E. A. Gray ◽  
G. J. Logan ◽  
I. E. Alexander ◽  
S. Poulton ◽  
T. Roscioli ◽  
...  
Keyword(s):  
T Cell ◽  
Splice Site ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Common Gamma Chain ◽  
Intronic Splice Site

Suspected Atypical Common Gamma Chain Severe Combined Immunodeficiency

2006 ◽  
Vol 117 (2) ◽  
pp. S288
Author(s):  
A. Chandra ◽  
D. Webster ◽  
K.C. Gilmour ◽  
D.S. Kumararatne ◽  
A. Thrasher
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Common Gamma Chain

Mutations in the gene for the common gamma chain (γc) in X-linked severe combined immunodeficiency

1998 ◽  
Vol 103 (6) ◽  
pp. 730-731 ◽  
Author(s):  
Sebastian D. Fugmann ◽  
Susanna Müller ◽  
Wilhelm Friedrich ◽  
Claus R. Bartram ◽  
K. Schwarz
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Common Gamma Chain ◽  
The Common

scholarly journals Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID

2021 ◽  
Vol 12 ◽  
Author(s):  
Jolanda Steininger ◽  
Alexander Leiss-Piller ◽  
Christoph B. Geier ◽  
Raphael Rossmanith ◽  
Reem Elfeky ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Splice Site ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
Cell Recovery ◽  
Hematopoietic Stem

Mutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts and hypogammaglobulinemia. SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by hematopoietic stem cell transplantation (HSCT) or gene therapy. We herein describe a male infant with X-linked severe combined immunodeficiency (X-SCID) diagnosed at 5 months of age. Genetic testing revealed a novel C to G missense mutation in exon 1 resulting in a 3’ splice site disruption with premature stop codon and aberrant IL2 receptor signaling. Following the diagnosis of X-SCID, the patient subsequently underwent a TCRαβ/CD19-depleted haploidentical HSCT. Post transplantation the patient presented with early CD8+ T cell recovery with the majority of T cells (>99%) being non-donor T cells. Genetic analysis of CD4+ and CD8+ T cells revealed a spontaneous 14 nucleotide insertion at the mutation site resulting in a novel splice site and restoring the reading frame although defective IL2RG function was still demonstrated. In conclusion, our findings describe a spontaneous second-site mutation in IL2RG as a novel cause of somatic mosaicism and early T cell recovery following haploidentical HSCT.

scholarly journals Case Report: Interleukin-2 Receptor Common Gamma Chain Defect Presented as a Hyper-IgE Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Brahim Belaid ◽  
Lydia Lamara Mahammed ◽  
Aida Mohand Oussaid ◽  
Melanie Migaud ◽  
Yasmine Khadri ◽  
...  
Keyword(s):  
T Cell ◽  
Functional Characterization ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Surface Expression ◽  
T Cell Subsets ◽  
Gamma Chain ◽  
Gene Encoding ◽  
Common Gamma Chain ◽  
Novel Therapeutic Strategies

X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2Rγ or γc) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A; p. Asp39Asn) of IL2RG in a 7-year-old boy. The patient suffered from recurrent sinopulmonary infections and refractory eczema. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. Surface expression of IL-2Rγ was reduced on his lymphocytes. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Further analysis revealed a decreased percentage of CD4+ T cells capable of secreting IFN-γ, but not IL-4 or IL-17. Studies on the functional consequences of IL-2Rγ variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies.

Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4090-4097 ◽  
Author(s):  
Carsten Speckmann ◽  
Ulrich Pannicke ◽  
Elisabeth Wiech ◽  
Klaus Schwarz ◽  
Paul Fisch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Intrinsic Defect ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Susceptibility To Infection

Abstract X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5-year-old boy with mild susceptibility to infection who was investigated for a mutation in IL2RG due to persistent natural killer (NK)– and T-cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK, and epithelial cells, whereas α/β and γ/δ T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T-cell precursor. This genetic correction in T cells resulted in a diverse T-cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T-cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow up and early consideration of hematopoietic stem cell transplantation (HSCT).

Interleukin-2 receptor common gamma chain (IL2RG) defects present a diagnostic challenge

2018 ◽  
Vol 5 (4) ◽  
pp. 130-134
Author(s):  
Caroline Weisser ◽  
Dennis E. Bulman ◽  
Kayla Flamenbaum ◽  
Maian Roifman
Keyword(s):  
Genetic Analysis ◽  
Severe Combined Immunodeficiency ◽  
Genetic Defect ◽  
Interleukin 2 ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Gene Encoding ◽  
Common Gamma Chain ◽  
Interleukin 2 Receptor ◽  
The Common

Background: The protein encoded by interleukin-2 receptor common gamma chain (IL2RG) is an important signaling component of many interleukin receptors, including those of interleukin-2, -4, -7, and -21, known as the common gamma chain. Mutations in the gene encoding the common gamma chain of the interleukin-2 receptor cause X-linked severe combined immunodeficiency (SCID). In this report, we present an unknown genetic defect of a patient diagnosed with SCID whose genetic analysis was performed 2 decades later. Methods: Whole genome sequencing and Sanger confirmation were used to identify a novel frameshift mutation in IL2RG. Massively parallel sequencing of genes associated with SCID were performed on the patient’s mother and sister. Results: Next generation sequencing techniques identified a heterozygous frame-shift deletion in the gene encoding the common gamma chain of IL2RG in our patient. The patient’s mother had a low level mosaicism for the same deletion. The sister had no detectable deletion. Conclusion: We have identified a novel mutation in IL2RG resulting in an X-linked SCID phenotype. The genetic analysis of the patient’s mother revealed a mosaicism which was not passed on to his sister. The importance of genetic analysis in family members and SCID patients with an unknown genetic defect should be emphasized for family planning and subsequent genetic counseling. Statement of novelty: Genetic testing is an extremely important component in evaluating severe combined immunodeficiency as it impacts treatment course and prognosis, and allows for genetic analysis and counselling of family members.

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