RAG Deficiency: Two Genes, Many Diseases

Delmonte, Ottavia M.; Schuetz, Catharina; Notarangelo, Luigi D.

doi:10.1007/s10875-018-0537-4

Cited by 93 publications

(82 citation statements)

References 93 publications

(130 reference statements)

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“…Therefore, we proposed that this phenotype be defined as “combined immunodeficiency with granuloma and/or autoimmunity” (CID‐G/AI) . In a series of 68 patients with CID‐G/AI included in a recent review, we observed that autoimmune cytopenias were particularly common, being found in 53% of the patients . However, severe vasculitis and organ‐specific autoimmunity affecting gut, liver, thyroid, kidney, and muscles.…”

Section: Spectrum Of Clinical Manifestations Caused By Rag Gene Defectsmentioning

confidence: 99%

“…T cells are usually present in lower number, and the proportion of naïve T cells is also reduced; however, in vitro T‐cell proliferation to mitogens is often normal or modestly reduced. Circulating B cells are present in variable number; immunoglobulin serum levels are often normal but may also be low or high, and specific antibody responses may be variably affected . Finally, these patients produce a broad spectrum of autoantibodies; neutralizing anti‐cytokine antibodies directed against interferon‐α and IFN‐ω has been reported, especially in patients with a history of varicella zoster virus infection …”

Section: Spectrum Of Clinical Manifestations Caused By Rag Gene Defectsmentioning

confidence: 99%

“…This may be even more of a problem in patients with CID‐G/AI, where such competition would also extend to more mature T‐ and B‐cell subsets. Limited data are available on the outcome of HCT in this group of patients . Of 26 patients reported in the literature who have received HCT because of CID‐G/AI, 18 (69.2%) were reported to be alive with a median follow‐up of 9 months.…”

Section: Treatment Of Rag Deficiency: From Hematopoietic Cell Transplmentioning

confidence: 99%

“…This translates in a variable degree of impairment of T‐ and B‐cell development, affecting composition and diversity of the immune repertoire and immune homeostasis. Consequently, RAG mutations have been associated with severe combined immunodeficiency with absence of T and B cells (T − B − SCID), Omenn syndrome (OS) with presence of oligoclonal and activated T cells infiltrating and damaging target tissues, atypical SCID (AS) with residual presence of oligoclonal T (and occasionally, B) cells, and combined immunodeficiency associated with granulomas and/or autoimmunity (CID‐G/AI) . Overall, recognition of this broad spectrum of clinical and immunological phenotypes underpins the critical role of the RAG complex in immune homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…defects, in which a similar phenomenon may reflect the existence of LOF and GOF alleles, 2 with residual presence of oligoclonal T (and occasionally, B) cells, and combined immunodeficiency associated with granulomas and/ or autoimmunity (CID-G/AI). 3 Overall, recognition of this broad spectrum of clinical and immunological phenotypes underpins the critical role of the RAG complex in immune homeostasis. Here, we will discuss recent advances in the mechanisms underlying the pathophysiology of the immune dysregulation associated with hypomorphic RAG mutations in patients and in animal models.…”

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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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Section: Spectrum Of Clinical Manifestations Caused By Rag Gene Defectsmentioning

confidence: 99%

Section: Spectrum Of Clinical Manifestations Caused By Rag Gene Defectsmentioning

confidence: 99%

Section: Treatment Of Rag Deficiency: From Hematopoietic Cell Transplmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

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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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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Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene

Goldberg

Simon

Rechavi

et al. 2020

Pediatric Blood & Cancer

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All coauthors have reviewed the manuscript and have contributed in a substantive and intellectual manner to the work described. * Orna Steinberg-Shemer and Raz Somech had equal contribution. AbstractBackground: The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature. Methods: Two patients with neutropenia underwent hematological, immunological, and genetic work-up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole-exome sequencing, and in silico proteomic analysis. Results: Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life-threatening infection requiring leg amputation. Immunological and hematological work-up showed isolated neutropenia with normal lymphocyte subpopulations,immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in-frame deletion in the SRP54 gene, c.342-344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability. Conclusions:We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene. K E Y W O R D Scongenital neutropenia, signal recognition particle, SRP54, variable expressivity

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RAG Deficiency: Two Genes, Many Diseases

Cited by 93 publications

References 93 publications

RAG gene defects at the verge of immunodeficiency and immune dysregulation

RAG gene defects at the verge of immunodeficiency and immune dysregulation

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

Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene

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