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

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, Om...

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Published in:	Human molecular genetics 2015-12, Vol.24 (25), p.7361-7372
Main Authors:	Volk, Timo, Pannicke, Ulrich, Reisli, Ismail, Bulashevska, Alla, Ritter, Julia, Björkman, Andrea, Schäffer, Alejandro A, Fliegauf, Manfred, Sayar, Esra H, Salzer, Ulrich, Fisch, Paul, Pfeifer, Dietmar, Di Virgilio, Michela, Cao, Hongzhi, Yang, Fang, Zimmermann, Karin, Keles, Sevgi, Caliskaner, Zafer, Güner, S Ükrü, Schindler, Detlev, Hammarström, Lennart, Rizzi, Marta, Hummel, Michael, Pan-Hammarström, Qiang, Schwarz, Klaus, Grimbacher, Bodo
Format:	Article
Language:	eng
Subjects:	B-Lymphocytes - metabolism Child Child, Preschool Endonucleases Female Humans Immunoglobulin A - metabolism Male Medicin och hälsovetenskap Mutation - genetics Nuclear Proteins - genetics Severe Combined Immunodeficiency - genetics
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Summary:	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.
ISSN:	0964-6906 1460-2083 1460-2083