A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Kuijpers, Taco W.; Leeuwen, Ester M. M. van; Barendregt, Barbara H.; Klarenbeek, Paul L.; Kerk, Daan J. aan de; Baars, Paul A.; Jansen, Machiel H.; Vries, Niek de; Lier, R. A. W. Van; Burg, Mirjam van der

doi:10.3324/haematol.2012.077511

Cited by 32 publications

(34 citation statements)

References 49 publications

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“…For this reason, and because cases of X-SCID with revertant mosaicism have been reported before, we favor the explanation that the wildtype alleles found in the T and NK cells of the patient derived from one or multiple in vivo spontaneous reversion events that led to revertant somatic mosaicism To the best of our knowledge, this patient is the seventh reported case of X-SCID with revertant somatic mosaicism. The characteristics of each reported case are summarized in Table 1 [3,[7][8][9][10][11]. Each case was considered to be atypical X-SCID because T and B cells were present.…”

Section: Discussionmentioning

confidence: 99%

“…Hypomorphic mutations, which impair but do not abrogate protein function, obscure and can even change the clinical presentation of the disease [2]. Somatic mosaicism, in which a patient has somatic cell populations of different genotypes, attenuates the severity of the disease [3]. Thus, obtaining a definite diagnosis in a patient with such a mutation is challenging.…”

Section: Introductionmentioning

confidence: 97%

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Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism

et al. 2015

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Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism

et al. 2015

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“…In four previously reported cases of spontaneous reversion in IL2RG [12-15], only CD3+ T cells demonstrated reversion to wild-type while all other lineages examined remained mutant. This is the first identified case of X-SCID in which the reversion is found in CD19+ B cells as well as T-cells, indicating a reversion event at the level of common lymphoid progenitor.…”

Section: Discussionmentioning

confidence: 99%

IL2RG Reversion Event in a Common Lymphoid Progenitor Leads to Delayed Diagnosis and Milder Phenotype

et al. 2015

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Severe combined immunodeficiency (SCID) is most frequently caused by mutations in the cytokine receptor common gamma chain, CD132, encoded by the X-linked gene, IL2RG. Most patients present in the first year of life with failure to thrive, severe, opportunistic infections and absence of CD3+ T cells. We present a patient with pediatric illness and a diagnosis of combined variable immune deficiency (CVID) who was diagnosed at age 23 with an inherited IL2RG mutation causing loss of signal transduction through CD132. His peripheral blood included CD3/CD4 and CD3/CD8 positive cells as well as low levels of CD19+ B cells containing a reversion to the wildtype IL2RG allele. The reversion, which was not present at birth, may account for his mild phenotype and late diagnosis.

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“…Gene sequence analysis was followed as previously described (Kuijpers et al 2013;Puel et al 1998;Sperati et al 2009). …”

Section: Gene Sequence Analysismentioning

confidence: 99%

A novel common gamma chain mutation in a Chinese family with X-linked severe combined immunodeficiency (X-SCID; T−NK−B+)

Tan

Lei

et al. 2015

Immunogenetics

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X-linked severe combined immunodeficiency (X-SCID) is one of the most common causes of primary immunodeficiencies in humans. A 4-month-old boy with recurrent pulmonary infection had decreased numbers of CD3(+), CD4(+), CD8(+) T lymphocytes, and NK cells and increased levels of CD19(+) B cells but no memory B cells or plasma cells. The production of cytokines by T cells and the activation of T and B cells were either absent or inefficient. While B cell levels were high, they were all IgM-positive, and the secretion of all Ig isotypes by activated B cells in vitro was defective. Genomic DNA sequencing revealed that the patient had missense mutations in the IL2RG (exon 5, 718 T > C) and IL7R genes (exon 2, 197 T > C; exon 4, 412G > A). Although the patient's father and one of his sisters have the same missense homozygous mutations of the IL7R gene, neither of them exhibited the immunological phenotype of SCID. The results indicate that the IL2RG gene mutation or a combination of the IL7R and IL2RG mutations in the sick boy had resulted in T(-)NK(-)B(+) SCID.

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A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Cited by 32 publications

References 49 publications

Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism

Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism

IL2RG Reversion Event in a Common Lymphoid Progenitor Leads to Delayed Diagnosis and Milder Phenotype

A novel common gamma chain mutation in a Chinese family with X-linked severe combined immunodeficiency (X-SCID; T−NK−B+)

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