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

Authors: Volk, T  Pannicke, U  Reisli, I  Bulashevska, A  Ritter, J  Bjorkman, A  Schaffer, AA  Fliegauf, M  Sayar, EH  Salzer, U  Fisch, P  Pfeifer, D  Di Virgilio, M  Cao, H  Yang, F  Zimmermann, K  Keles, S  Caliskaner, Z  Guner, SU  Schindler, D  Hammarstrom, L  Rizzi, M  Hummel, M  Pan-Hammarstrom, Q  Schwarz, K  Grimbacher, B 
Citation: Volk T, etal., Hum Mol Genet. 2015 Dec 20;24(25):7361-72. doi: 10.1093/hmg/ddv437. Epub 2015 Oct 16.
Pubmed: (View Article at PubMed) PMID:26476407
DOI: Full-text: DOI:10.1093/hmg/ddv437

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 naive 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.

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RGD Object Information
RGD ID: 11251730
Created: 2016-06-20
Species: All species
Last Modified: 2016-06-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.