title: Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes.
abstract: BACKGROUND
  V(D)J recombination takes place during lymphocyte development to generate a large repertoire of T- and B-cell receptors. Mutations in recombination-activating gene 1 (RAG1) and RAG2 result in loss or reduction of V(D)J recombination. It is known that different mutations in RAG genes vary in residual recombinase activity and give rise to a broad spectrum of clinical phenotypes.
  
  
  OBJECTIVE
  We sought to study the immunologic mechanisms causing the clinical spectrum of RAG deficiency.
  
  
  METHODS
  We included 22 patients with similar RAG1 mutations (c.519delT or c.368_369delAA) resulting in N-terminal truncated RAG1 protein with residual recombination activity but presenting with different clinical phenotypes. We studied precursor B-cell development, immunoglobulin and T-cell receptor repertoire formation, receptor editing, and B- and T-cell numbers.
  
  
  RESULTS
  Clinically, patients were divided into 3 main categories: T(-)B(-) severe combined immunodeficiency, Omenn syndrome, and combined immunodeficiency. All patients showed a block in the precursor B-cell development, low B- and T-cell numbers, normal immunoglobulin gene use, limited B- and T-cell repertoires, and slightly impaired receptor editing.
  
  
  CONCLUSIONS
  This study demonstrates that similar RAG mutations can result in similar immunobiological effects but different clinical phenotypes, indicating that the level of residual recombinase activity is not the only determinant for clinical outcome. We postulate a model in which the type and moment of antigenic pressure affect the clinical phenotypes of these patients.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: IJspeert
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Gertjan J
authors.initials: GJ
authors.lastname: Driessen
authors.affiliation: Department of Blood Cell Research, Stichting Sanquin Bloedvoorziening, Amsterdam, The Netherlands.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Moorhouse
authors.affiliation: Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Nico G
authors.initials: NG
authors.lastname: Hartwig
authors.affiliation: Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Wolska-Kusnierz
authors.affiliation: Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kalwak
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Pituch-Noworolska
authors.affiliation: Department of Clinical Immunology, Russian State Children's Hospital, Moscow, Russia.
authors.forename: Irina
authors.initials: I
authors.lastname: Kondratenko
authors.affiliation: Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht and Wilhelmina Children's Hospital, Utrecht, The Netherlands.
authors.forename: Joris M
authors.initials: JM
authors.lastname: van Montfrans
authors.affiliation: Department of Pediatric Hematology and Oncology, Teaching Hospital Motol and 2nd Medical School, Charles University, Prague, Czech Republic.
authors.forename: Ester
authors.initials: E
authors.lastname: Mejstrikova
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arjan C
authors.initials: AC
authors.lastname: Lankester
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.affiliation: Department of Cell Biology and Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.affiliation: Department of Bioinformatics, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Stubbs
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address: m.vanderburg@erasmusmc.nl.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002675:Child, Preschool; D022801:Complementarity Determining Regions / Q000235:genetics; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D018655:Lymphocyte Count; D009154:Mutation; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D022801:Complementarity Determining Regions; D018398:Homeodomain Proteins; D007143:Immunoglobulin Heavy Chains; C064658:RAG-1 protein
keywords: B- and T-cell receptor repertoire; RAG deficiency; V(D)J recombination; autoimmunity; immune repertoire analysis; next generation sequencing; receptor editing