Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy

• Published in: Clinical immunology (Orlando, Fla.) Vol. 179; pp. 1 - 7
• Main Authors: Schröder, Claudia, Baerlecken, Niklas, Pannicke, Ulrich, Dörk, Thilo, Witte, Torsten, Jacobs, Roland, Stoll, Matthias, Schwarz, Klaus, Grimbacher, Bodo, Schmidt, Reinhold E, Atschekzei, Faranaz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2017
• Subjects: Adult; Allergy and Immunology; B-Lymphocytes - immunology; Biopsy; Brain - diagnostic imaging; Brain - pathology; Cell Proliferation; Combined immunodeficiency (CID); Common variable immunodeficiency (CVID); Homeodomain Proteins - genetics; Humans; Immunoglobulins - blood; Immunologic Deficiency Syndromes - blood; Immunologic Deficiency Syndromes - diagnostic imaging; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Leukoencephalopathy, Progressive Multifocal - blood; Leukoencephalopathy, Progressive Multifocal - diagnostic imaging; Leukoencephalopathy, Progressive Multifocal - genetics; Leukoencephalopathy, Progressive Multifocal - immunology; Lymphocyte Count; Magnetic Resonance Imaging; Male; Mutation; Progressive multifocal leukoencephalopathy (PML); Receptors, Antigen, T-Cell - immunology; Recombination activation gene 1 (RAG1); T-Lymphocytes - immunology; V(D)J Recombination; Common v ariable i mmunodeficiency (CVID); R ecombination activation gene 1 ( RAG1); Combined immunodeficiency (CID); Progressive multifocal leukoencephalopathy (PML); Recombination activation gene 1 (RAG1); Common variable immunodeficiency (CVID)
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2016.12.013

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.