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

Tools

Item Type:	Article
Title:	DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency
Creators Name:	Volk, T., Pannicke, U., Reisli, I., Bulashevska, A., Ritter, J., Björkman, A., Schäffer, A.A., Fliegauf, M., Sayar, E.H., Salzer, U., Fisch, P., Pfeifer, D., Di Virgilio, M., Cao, H., Yang, F., Zimmermann, K., Keles, S., Caliskaner, Z., Güner, S.Ü., Schindler, D., Hammarström, L., Rizzi, M., Hummel, M., Pan-Hammarstroem, Q., 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
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	24
Number:	25
Page Range:	7361-7372
Date:	20 December 2015
Official Publication:	https://doi.org/10.1093/hmg/ddv437
PubMed:	View item in PubMed

Repository Staff Only: item control page