Intronic point mutation in the IL2RG gene causing X-linked severe combined immunodeficiency

Tassara, Carla; Pepper, Amy E.; Puck, Jennifer M.

doi:10.1093/hmg/4.9.1693

Cited by 22 publications

(15 citation statements)

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“…10 Mutations found in 240 consecutive patients with IL2RG mutations enrolled between 1987 and 2006 were used to establish rates of new versus recurrent mutations. [11][12][13][14][15][16][17] Samples from 59 SCID patients with known SCID mutations and 50 carrier parents 10 -19 (J. Puck, unpublished data) were used to assess array performance. An additional 10 samples from SCID patients of unknown genotype were tested by array prior to standard dideoxy sequence determination.…”

Section: Patient Samplesmentioning

confidence: 99%

“…10,[12][13][14][15][16][17] The mutations in IL2RG in this cohort were listed by date of case referral and divided into 12 groups of 20 cases, as shown in Figure 1. The number of unique mutations as each successive group was added (orange boxes, left axis) continued to grow and did not reach a plateau, even though cases with recurrent mutations also rose (green circles, left axis).…”

Section: Proportion Of Unique Versus Recurrent Mutationsmentioning

confidence: 99%

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Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray

Lebet

Chiles²,

Hsu

et al. 2008

Genetics in Medicine

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Purpose: Mutation diagnosis of severe combined immunodeficiency is challenging because of the multiplicity of disease genes and large number of disease-causing mutations, including unique ones that continue to be found.A resequencing microarray could facilitate mutation detection, increasing the chance of diagnosing infants early for optimal rescue by hematopoietic stem cell transplantation. Methods: After analyzing cumulative mutations, we developed a custom Affymetrix GeneChip® microarray including probes representing exons and flanking regions of severe combined immunodeficiency disease genes. DNA samples were analyzed by array versus standard dideoxy genomic sequencing. We tested males and their mothers with X-linked IL2RG variants and patients and carriers with autosomal variants in IL7R, JAK3, and DCLRE1C. Results: New, unique severe combined immunodeficiency mutations are frequent. Resequencing array call rates of 95-98% exceeded GeneChip product specifications, and all of 47 point mutations in known samples were detected, as were the sites of 12 of 22 disease-causing insertions and deletions. Each gene had particular nucleotides that were often not called correctly and had to be excluded from analysis; exclusion rates ranged from 0.4% (hemizygous IL2RG) to 9.2% (heterozygous JAK3). Conclusion:Microarray resequencing is a promising technology for severe combined immunodeficiency mutation diagnosis that

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Section: Patient Samplesmentioning

confidence: 99%

Section: Proportion Of Unique Versus Recurrent Mutationsmentioning

confidence: 99%

Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray

Lebet

Chiles²,

Hsu

et al. 2008

Genetics in Medicine

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“…The second common category of mutations leading to immunodeficiency is the lack of the common gamma chain (γc) which is an integral part of receptors required for the response to the cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. This leads to a failure in various cell types to mature and/or expand, including T cells, B cells, and natural killer (NK) cells [11], [12], [13]. Other mutations resulting in decreased NK cell activity (e.g., non-obese diabetic or NOD) have also been shown to support improved xenoengraftment [14].…”

Section: Introductionmentioning

confidence: 99%

Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

et al. 2011

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Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2−/−γc−/−, NOD/SCID, NOD/SCIDγc−/− and NOD/SCIDβ2m−/− strains. Transplantation of these mice with CD34+ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1−/−γ−/− strain for engraftment by human fetal liver derived CD34+ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2−/−γc−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1−/−γc−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting.

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“…Defects in the gene coding for ␥ c (il2rg) cause an X-linked severe combined immune deficiency characterized by several immune defects, including an absence of mature NK cells (1,2). The common cytokine receptor ␥ chain is essential for the function of at least six cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (3).…”

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confidence: 99%

Roles for Common Cytokine Receptor γ-Chain-Dependent Cytokines in the Generation, Differentiation, and Maturation of NK Cell Precursors and Peripheral NK Cells in Vivo

Vosshenrich

Ranson

Samson

et al. 2005

The Journal of Immunology

249

234

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NK cells differentiate in adult mice from bone marrow hemopoietic progenitors. Cytokines, including those that signal via receptors using the common cytokine receptor γ-chain (γc), have been implicated at various stages of NK cell development. We have previously described committed NK cell precursors (NKPs), which have the capacity to generate NK cells, but not B, T, erythroid, or myeloid cells, after in vitro culture or transfer to a fetal thymic microenvironment. NKPs express the CD122 Ag (β chain of the receptors for IL-2/IL-15), but lack other mature NK markers, including NK1.1, CD49b (DX5), or members of the Ly49 gene family. In this report, we have analyzed the roles for γc-dependent cytokines in the generation of bone marrow NKP and in their subsequent differentiation to mature NK cells in vivo. Normal numbers of NKPs are found in γc-deficient mice, suggesting that NK cell commitment is not dependent on IL-2, IL-4, IL-7, IL-9, IL-15, or IL-21. Although IL-2, IL-4, and IL-7 have been reported to influence NK cell differentiation, we find that mice deficient in any or all of these cytokines have normal NK cell numbers, phenotype, and effector functions. In contrast, IL-15 plays a dominant role in early NK cell differentiation by maintaining normal numbers of immature and mature NK cells in the bone marrow and spleen. Surprisingly, the few residual NK cells generated in absence of IL-15 appear relatively mature, expressing a variety of Ly49 receptors and demonstrating lytic and cytokine production capacity.

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Intronic point mutation in the IL2RG gene causing X-linked severe combined immunodeficiency

Cited by 22 publications

References 0 publications

Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray

Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray

Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

Roles for Common Cytokine Receptor γ-Chain-Dependent Cytokines in the Generation, Differentiation, and Maturation of NK Cell Precursors and Peripheral NK Cells in Vivo

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