Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity

Henderson, Lauren A.; Frugoni, Francesco; Hopkins, Gregory; Boer, Helen de; Pai, Sung-Yun; Lee, Yu Nee; Walter, Jolán E.; Hazen, Melissa; Notarangelo, Luigi D.

doi:10.1016/j.jaci.2013.06.032

Cited by 58 publications

(47 citation statements)

References 12 publications

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“…30). It remains to be studied whether similar findings are observed also in patients with CID–G/AI who carry missense mutations (F974L, R975Q and R975W) 9,34,35 that affect a coding flank-sensitive domain of RAG1 (REF. 60).…”

Section: Immune Dysregulation Of Rag Deficiencymentioning

confidence: 79%

Human RAG mutations: biochemistry and clinical implications

et al. 2016

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The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate the V(D)J recombination process, which ultimately enables the generation of T cells and B cells with a diversified repertoire of antigen-specific receptors. Mutations of the RAG genes in humans are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to autoimmunity. Recently, novel insights into the phenotypic diversity of this disease have been provided by resolving the crystal structure of the RAG complex, by developing novel assays to test recombination activity of the mutant RAG proteins and by characterizing the molecular and cellular basis of immune dysregulation in patients with RAG deficiency.

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Section: Immune Dysregulation Of Rag Deficiencymentioning

confidence: 79%

Human RAG mutations: biochemistry and clinical implications

et al. 2016

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“…Defects in signaling or in T-cell receptor recombination or editing may result in both a deficit of FOXP3-positive regulatory T cells (Tregs) and an incomplete development of autoimmune regulator transcription factor-expressing medullary thymus epithelial cells that result in peripheral and central tolerance defects. 22 Thus, many classic T-cell disorders such as combined immunodeficiencies (CIDs) that lack naïve T cells based on hypomorphic mutations in genes usually associated with severe CID (SCID; ie, leaky SCIDs such as RAG1, RAG2, adenosine desaminase, artemis, and purine nucleoside phosphorylase [23][24][25][26][27] ) and well-known syndromes with immunodeficiency such as WAS, WAS protein-interacting protein deficiency, and 22q11 microdeletion syndrome may show some extent of autoimmunity as a result of autoreactive T cells and reduced T-cell regulation. Furthermore, certain T-cell signaling defects that may cause SCID or CID, such as ORAI-1, STIM-1, MAGT1, STK4, or LCK deficiencies as well as activating mutations of PI3KD, predispose to autoimmunity including cytopenias.…”

Section: Autoimmune-mediated Cytopenia In Pidmentioning

confidence: 99%

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Seidel

2014

Blood

128

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Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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“…Also, De Ravin et al [19] reported hypomorphic RAG mutations presented with destructive midline granulomatous disease. The pleomorphic manifestations of RAG deficiency are partially explained by residual RAG activity, with null mutations producing an SCID phenotype and hypomorphic mutations presenting more variably [18]. The presented article adds a new case expanding the spectrum of RAG1 gene deficiency.…”

Section: Discussionmentioning

confidence: 92%

“…Null mutations of RAG1 and RAG2 genes result in the T-B-SCID phenotype. However, hypomorphic RAG mutations have been associated with a spectrum of clinical and immunologic phenotypes that include OS with erythroderma, lymphadenopathy, eosinophilia, increased serum IgE levels, and the presence of autologous, oligoclonal, and activated T lymphocytes; leaky/atypical SCID, with varying numbers of T and B cells but without the typical features of OS; delayed-onset combined immune deficiency with granuloma and/or autoimmunity (CID-G/A) [15]; SCID with expansion of γδ T lymphocytes [16], which us often associated with cytomegalovirus infection; and in a single case of idiopathic CD4 + T cell lymphopenia [17], presenting with extensive chickenpox and recurrent pneumonia, and early onset-autoimmunity [18]. Also, De Ravin et al [19] reported hypomorphic RAG mutations presented with destructive midline granulomatous disease.…”

Section: Discussionmentioning

confidence: 99%

Atypical Severe Combined Immunodeficiency Caused by a Novel Homozygous Mutation In Rag1 Gene in a Girl who Presented with Pyoderma Gangrenosum: A Case Report and Literature Review

et al. 2014

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Severe combined immunodeficiency (SCID) is a heterogeneous group of inherited defects involving the development of T- and/or B-lymphocytes. We report a female with atypical severe combined immunodeficiency caused by a novel homozygous mutation at cDNA position 2290 (c.2290C > T) in exon 2 of the RAG1 gene. The patient presented with bronchopneumonia, pyoderma gangrenosum (PG), pancytopenia and splenomegaly. She presented to us with pancytopenia and splenomegaly at the age of 11. Her condition was complicated by PG on left lower ankle at the age of 12. She experienced bronchopneumonia at the age of 15. She was diagnosed with RAG1 deficiency at the age of 16. Her immunological presentation included leucopenia and diminished number of B cells.

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Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity

Cited by 58 publications

References 12 publications

Human RAG mutations: biochemistry and clinical implications

Human RAG mutations: biochemistry and clinical implications

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Atypical Severe Combined Immunodeficiency Caused by a Novel Homozygous Mutation In Rag1 Gene in a Girl who Presented with Pyoderma Gangrenosum: A Case Report and Literature Review

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