title: V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.
abstract: Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.
authors.affiliation: Department of Human Genome and Multifactorial Disease, Istituto di Tecnologie, Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Segrate, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: C
authors.initials: C
authors.lastname: Sobacchi
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
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authors.initials: F
authors.lastname: Bozzi
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authors.initials: TG
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authors.initials: PD
authors.lastname: Arkwright
authors.forename: M
authors.initials: M
authors.lastname: Baniyash
authors.forename: E G
authors.initials: EG
authors.lastname: Brooks
authors.forename: M E
authors.initials: ME
authors.lastname: Conley
authors.forename: P
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authors.lastname: Cortes
authors.forename: M
authors.initials: M
authors.lastname: Duse
authors.forename: A
authors.initials: A
authors.lastname: Fasth
authors.forename: A M
authors.initials: AM
authors.lastname: Filipovich
authors.forename: A J
authors.initials: AJ
authors.lastname: Infante
authors.forename: A
authors.initials: A
authors.lastname: Jones
authors.forename: E
authors.initials: E
authors.lastname: Mazzolari
authors.forename: S M
authors.initials: SM
authors.lastname: Muller
authors.forename: S
authors.initials: S
authors.lastname: Pasic
authors.forename: G
authors.initials: G
authors.lastname: Rechavi
authors.forename: M G
authors.initials: MG
authors.lastname: Sacco
authors.forename: S
authors.initials: S
authors.lastname: Santagata
authors.forename: M L
authors.initials: ML
authors.lastname: Schroeder
authors.forename: R
authors.initials: R
authors.lastname: Seger
authors.forename: D
authors.initials: D
authors.lastname: Strina
authors.forename: A
authors.initials: A
authors.lastname: Ugazio
authors.forename: J
authors.initials: J
authors.lastname: Väliaho
authors.forename: M
authors.initials: M
authors.lastname: Vihinen
authors.forename: L B
authors.initials: LB
authors.lastname: Vogler
authors.forename: H
authors.initials: H
authors.lastname: Ochs
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
authors.forename: W
authors.initials: W
authors.lastname: Friedrich
authors.forename: K
authors.initials: K
authors.lastname: Schwarz
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D016208:Databases, Factual; D005192:Family Health; D005260:Female; D016654:Genes, RAG-1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D008214:Lymphocytes / Q000276:immunology*; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins; D011247:Pregnancy; D011995:Recombination, Genetic; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000235:genetics; D013601:T-Lymphocytes / Q000637:transplantation
chemical_list: D004268:DNA-Binding Proteins; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064655:V(D)J recombination activating protein 2