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DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency

Item Type:Article
Title:DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency
Creators Name:Volk, T. and Pannicke, U. and Reisli, I. and Bulashevska, A. and Ritter, J. and Björkman, A. and Schäffer, A.A. and Fliegauf, M. and Sayar, E.H. and Salzer, U. and Fisch, P. and Pfeifer, D. and Di Virgilio, M. and Cao, H. and Yang, F. and Zimmermann, K. and Keles, S. and Caliskaner, Z. and Güner, S.Ü. and Schindler, D. and Hammarström, L. and Rizzi, M. and Hummel, M. and Pan-Hammarstroem, Q. and Schwarz, K. and Grimbacher, B.
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.
Keywords:B-Lymphocytes, Immunoglobulin A, Mutation, Nuclear Proteins, Severe Combined Immunodeficiency
Source:Human Molecular Genetics
Publisher:Oxford University Press
Page Range:7361-7372
Date:20 December 2015
Official Publication:https://doi.org/10.1093/hmg/ddv437
PubMed:View item in PubMed

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