title: Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy.
abstract: Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p.H375D and c.1430delC, p.F478Sfs*14), namely a missense variant and a frameshift deletion, of which the latter leads to a truncated RAG1 protein. The other allele revealed a previously described missense mutation (c.1420C>T, p.R474C, rs199474678). Functional analysis of the p.R474C variant in an in vitro V(D)J recombination assay exhibited reduced recombination activity compared to a wild-type control. Our findings suggest that mutations in RAG1, specifically the p.R474C variant, can be associated with relatively mild clinical symptoms or delayed occurrence of T cell and B cell deficiencies but may predispose to PML.
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schröder
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany.
authors.forename: Niklas Thomas
authors.initials: NT
authors.lastname: Baerlecken
authors.affiliation: Department of Transfusion Medicine, University of Ulm, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Jacobs
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stoll
authors.affiliation: Department of Transfusion Medicine, University of Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg - Hessen, Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Center for Chronic Immunodeficiency, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany.
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Germany. Electronic address: Atschekzei.Faranaz@mh-hannover.de.
authors.forename: Faranaz
authors.initials: F
authors.lastname: Atschekzei
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology; D001706:Biopsy; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D049109:Cell Proliferation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D007968:Leukoencephalopathy, Progressive Multifocal / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D060152:V(D)J Recombination
chemical_list: D018398:Homeodomain Proteins; D007136:Immunoglobulins; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein
keywords: Combined immunodeficiency (CID); Common variable immunodeficiency (CVID); Progressive multifocal leukoencephalopathy (PML); Recombination activation gene 1 (RAG1)