Document Detail

Hypomorphic Rag mutations can cause destructive midline granulomatous disease.
MedLine Citation:
PMID:  20489056     Owner:  NLM     Status:  MEDLINE    
Destructive midline granulomatous disease characterized by necrotizing granulomas of the head and neck is most commonly caused by Wegener granulomatosis, natural killer/T-cell lymphomas, cocaine abuse, or infections. An adolescent patient with myasthenia gravis treated with thymectomy subsequently developed extensive granulomatous destruction of midface structures, palate, nasal septum, airways, and epiglottis. His lymphocyte numbers, total immunoglobulin G level, and T-cell receptor (TCR) repertoire appeared normal. Sequencing of Recombination activating gene-1 (Rag1) showed compound heterozygous Rag1 mutations; a novel deletion with no recombinase activity and a missense mutation resulting in 50% Rag activity. His thymus was dysplastic and, although not depleted of T cells, showed a notable absence of autoimmune regulator (AIRE) and Foxp3(+) regulatory T cells. This distinct Rag-deficient phenotype characterized by immune dysregulation with granulomatous hyperinflammation and autoimmunity, with relatively normal T and B lymphocyte numbers and a diverse TCR repertoire expands the spectrum of presentation in Rag deficiency. This study was registered at as #NCT00128973.
Suk See De Ravin; Edward W Cowen; Kol A Zarember; Narda L Whiting-Theobald; Douglas B Kuhns; Netanya G Sandler; Daniel C Douek; Stefania Pittaluga; Pietro L Poliani; Yu Nee Lee; Luigi D Notarangelo; Lei Wang; Frederick W Alt; Elizabeth M Kang; Joshua D Milner; Julie E Niemela; Mary Fontana-Penn; Sara H Sinal; Harry L Malech
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2010-05-20
Journal Detail:
Title:  Blood     Volume:  116     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-27     Completed Date:  2010-09-30     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1263-71     Citation Subset:  AIM; IM    
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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MeSH Terms
Cells, Cultured
Forkhead Transcription Factors
Gene Rearrangement
Genes, Immunoglobulin
Granulomatous Disease, Chronic / etiology*,  pathology*,  surgery
Homeodomain Proteins / genetics*,  physiology*
Immunoglobulin G / immunology,  metabolism
Lymphocytes / immunology,  metabolism
Mutation, Missense / genetics*
Recombinases / metabolism
Severe Combined Immunodeficiency / etiology*,  pathology*
T-Lymphocytes, Regulatory / immunology,  metabolism,  pathology
Transcription Factors
Transgenes / physiology
Grant Support
Reg. No./Substance:
0/APECED protein; 0/FOXP3 protein, human; 0/Forkhead Transcription Factors; 0/Homeodomain Proteins; 0/Immunoglobulin G; 0/Recombinases; 0/Transcription Factors; 128559-51-3/RAG-1 protein

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