title: DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency.
abstract: Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Volk
authors.affiliation: Institute for Transfusion Medicine, University Ulm, Ulm, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.affiliation: Department of Pediatric Immunology and Allergy.
authors.forename: Ismail
authors.initials: I
authors.lastname: Reisli
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Alla
authors.initials: A
authors.lastname: Bulashevska
authors.affiliation: Institute of Pathology, Campus Benjamin Franklin, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Björkman
authors.affiliation: Department of Health and Human Services, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.affiliation: Department of Pediatric Immunology and Allergy.
authors.forename: Esra H
authors.initials: EH
authors.lastname: Sayar
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.affiliation: Center for Pathology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Max-Delbruck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.affiliation: Science and Technology Department, BGI-Shenzhen, Shenzhen, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Cao
authors.affiliation: Science and Technology Department, BGI-Shenzhen, Shenzhen, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Institute of Pathology, Campus Benjamin Franklin, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatric Immunology and Allergy.
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.affiliation: Department of Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
authors.forename: Zafer
authors.initials: Z
authors.lastname: Caliskaner
authors.affiliation: Department of Pediatric Immunology and Allergy.
authors.forename: S Ükrü
authors.initials: SÜ
authors.lastname: Güner
authors.affiliation: Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.affiliation: Institute of Pathology, Campus Benjamin Franklin, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Institute of Pathology, Campus Benjamin Franklin, Charité - University Medicine Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.affiliation: Institute for Transfusion Medicine, University Ulm, Ulm, Germany, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg, Hessen, Germany and.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, Freiburg, Germany, Institute of Immunity and Transplantation, University College London, Royal Free Campus, London, UK bodo.grimbacher@uniklinik-freiburg.de.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D009687:Nuclear Proteins; C426344:DCLRE1C protein, human; D004720:Endonucleases