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

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dc.contributor.authorVolk, Timo
dc.contributor.authorPannicke, Ulrich
dc.contributor.authorReisli, Ismail
dc.contributor.authorBulashevska, Alla
dc.contributor.authorRitter, Julia
dc.contributor.authorBjorkman, Andrea
dc.contributor.authorSchaeffer, Alejandro A.
dc.date.accessioned2024-02-23T14:21:00Z
dc.date.available2024-02-23T14:21:00Z
dc.date.issued2015
dc.departmentNEÜen_US
dc.description.abstractNull 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.en_US
dc.description.sponsorshipGerman 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 funden_US
dc.description.sponsorshipThis study was supported by the German Federal Ministry of Education and Research (BMBF 01EO1303). The authors are responsible for the contents of this publication. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. T.V. received funding from the MOTIVATE program of the medical faculty Freiburg sponsored by the Else Kroner Fresenius Foundation. M.D.V. is a Helmholtz Young Investigator (Helmholtz Association, Germany). P.F. received funds from the Deutsche Jose Carreras Leukamie Stiftung (DJCLS R10/34f). Q.P.H, A.B. and L.H. received grants from the Swedish Research Council and the Swedish Cancer Society. D.S.'s group was supported by the Schroeder-Kurth fund.en_US
dc.identifier.doi10.1093/hmg/ddv437
dc.identifier.endpage7372en_US
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.issue25en_US
dc.identifier.pmid26476407en_US
dc.identifier.scopus2-s2.0-84959253960en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage7361en_US
dc.identifier.urihttps://doi.org/10.1093/hmg/ddv437
dc.identifier.urihttps://hdl.handle.net/20.500.12452/13406
dc.identifier.volume24en_US
dc.identifier.wosWOS:000368373600017en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherOxford Univ Pressen_US
dc.relation.ispartofHuman Molecular Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleDCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiencyen_US
dc.typeArticleen_US

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