Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 25, Pages 7361-7372Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv437
Keywords
-
Funding
- German Federal Ministry of Education and Research [BMBF 01EO1303]
- Intramural Research Program of the National Institutes of Health, National Library of Medicine
- MOTIVATE program of the medical faculty Freiburg - Else Kroner Fresenius Foundation
- Deutsche Jose Carreras Leukamie Stiftung [DJCLS R10/34f]
- Swedish Research Council
- Swedish Cancer Society
- Schroeder-Kurth fund
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available