Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype

Tirosh, Irit; Yamazaki, Yasuhiro; Frugoni, Francesco; Ververs, Francesca A.; Allenspach, Eric J.; Burns, Siobhan O.; Al‐Herz, Waleed; Noroski, Lenora M.; Walter, Jolán E.; Gennery, Andrew R.; Burg, Mirjam van der; Notarangelo, Luigi D.; Lee, Yu Nee

doi:10.1016/j.jaci.2018.04.027

Cited by 38 publications

(49 citation statements)

References 38 publications

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“… as they suggested that early exposure to pathogens may induce T cell expansion that contribute to the phenotype. In the present study we observed some previously reported mutations which presented differently among our cohort; for example, the R229Q mutation in RAG2, that was considered a severe mutation with residual recombination activity of 8·9% , was found in five of our SCID patients and has been previously reported in patients with the OS phenotype . Similarly, the G35V that had 0·4% recombination activity presented with the classical SCID phenotype in five of our patients and had been previously reported in two OS patients .…”

Section: Discussionsupporting

confidence: 75%

“…A study by Tirosh et al . that measured the recombinase activity of RAG2 mutant proteins, revealed that the T215I variant had 67·2% of wild‐type recombinase activity, while the R229Q had only 8·9% residual activity. The T215I variant has a relatively high CADD‐PHRED score of 21·4 and is reported in the gnomAD database with an MAF of 0·002984, although it was as high as 0·02527 in South Asians, including 11 homozygous subjects.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population

Meshaal

Hawary

Elaziz

et al. 2018

Clinical and Experimental Immunology

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Summary Mutations affecting recombination activation genes RAG1 and RAG2 are associated with variable phenotypes, depending on the residual recombinase activity. The aim of this study is to describe a variety of clinical phenotypes in RAG‐deficient patients from the highly consanguineous Egyptian population. Thirty‐one patients with RAG mutations (from 28 families) were included from 2013 to 2017. On the basis of clinical, immunological and genetic data, patients were subdivided into three groups; classical T–B– severe combined immunodeficiency (SCID), Omenn syndrome (OS) and atypical SCID. Nineteen patients presented with typical T–B–SCID; among these, five patients carried a homozygous RAG2 mutation G35V and five others carried two homozygous RAG2 mutations (T215I and R229Q) that were detected together. Four novel mutations were reported in the T–B–SCID group; three in RAG1 (A565P, N591Pfs*14 and K621E) and one in RAG2 (F29S). Seven patients presented with OS and a novel RAG2 mutation (C419W) was documented in one patient. The atypical SCID group comprised five patients. Two had normal B cell counts; one had a previously undescribed RAG2 mutation (V327D). The other three patients presented with autoimmune cytopaenias and features of combined immunodeficiency and were diagnosed at a relatively late age and with a substantial diagnostic delay; one patient had a novel RAG1 mutation (C335R). PID disorders are frequent among Egyptian children because of the high consanguinity. RAG mutations stand behind several variable phenotypes, including classical SCID, OS, atypical SCID with autoimmunity and T–B+ CID.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population

Meshaal

Hawary

Elaziz

et al. 2018

Clinical and Experimental Immunology

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“…Overall, these assays have demonstrated that naturally occurring missense RAG mutations present a wide range of recombination activity, with robust, albeit not absolute correlation with the clinical and immunological phenotype . They have also helped demonstrate that some variants that had been reported in patients with SCID/OS, support wildtype levels of recombination activity, and therefore are presumably not disease causing, as shown for the RAG2 N474S variant …”

Section: Genotype‐phenotype Correlation In Rag Deficiencymentioning

confidence: 79%

“…To circumvent this problem, we have used a different approach in which Abelson virus transformed Rag1 −/− (or Rag2 −/− ) mouse pro‐B cells engineered to express an inverted green fluorescent protein (GFP) cassette flanked by RSS and an Em‐bcl2 transgene are transduced with retroviral vectors expressing either wildtype or mutant human RAG1 (hRAG1) or hRAG2. Upon treatment of cells with imatinib to maintain cells in G0‐G1 and enhance RAG expression, flow cytometric assessment of GFP is used to assess recombination activity of the RAG mutant. Furthermore, this assay also permits to analyze the efficiency of V(D)J recombination at the endogenous Ighc locus.…”

Section: Genotype‐phenotype Correlation In Rag Deficiencymentioning

confidence: 99%

“…Furthermore, this assay also permits to analyze the efficiency of V(D)J recombination at the endogenous Ighc locus. More recently, we have further modified the flow cytometry‐based assay by using bicistronic vectors that allow simultaneous expression of two RAG variants at 1:1 ratio . As the RAG complex is a heterotetramer, use of bicistronic vectors is especially important to assess the net effect of compound heterozygous missense mutations.…”

Section: Genotype‐phenotype Correlation In Rag Deficiencymentioning

confidence: 99%

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RAG gene defects at the verge of immunodeficiency and immune dysregulation

Villa

Notarangelo

2018

Immunological Reviews

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Summary Mutations of the Recombinase Activating Genes (RAG) in humans underlie a broad spectrum of clinical and immunological phenotypes that reflect different degrees of impairment of T and B cell development and alterations of mechanisms of central and peripheral tolerance. Recent studies have shown that this phenotypic heterogeneity correlates, albeit imperfectly, with different levels of recombination activity of the mutant RAG proteins. Furthermore, studies in patients and in newly developed animal models carrying hypomorphic RAG mutations have disclosed various mechanisms underlying immune dysregulation in this condition. Careful annotation of clinical outcome and immune reconstitution in RAG-deficient patients who have received hematopoietic stem cell transplantation has shown that progress has been made in the treatment of this disease, but new approaches remain to be tested to improve stem cell engraftment and durable immune reconstitution. Finally, initial attempts have been made to treat RAG deficiency with gene therapy.

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RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

2021

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The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T − B − SCID) and susceptibility to life-threatening, early-onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.

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Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype

Abstract: Our data support genotype-phenotype correlation in the setting of RAG2 deficiency. The assay described can be used to define the possible disease-causing role of novel RAG2 variants and might help predict the severity of the clinical phenotype.

Cited by 38 publications

References 38 publications

Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population

Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population

RAG gene defects at the verge of immunodeficiency and immune dysregulation

RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches

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