Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency

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dc.contributor.authorFelgentreff, Kerstin
dc.contributor.authorLee, Yu Nee
dc.contributor.authorFrugoni, Francesco
dc.contributor.authorDu, Likun
dc.contributor.authorvan der Burg, Mirjam
dc.contributor.authorGiliani, Silvia
dc.contributor.authorTezcan, Ilhan
dc.date.accessioned2024-02-23T14:12:29Z
dc.date.available2024-02-23T14:12:29Z
dc.date.issued2015
dc.departmentNEÜen_US
dc.description.abstractBackground: The endonuclease ARTEMIS, which is encoded by the DCLRE1C gene, is a component of the nonhomologous end-joining pathway and participates in hairpin opening during the V(D)J recombination process and repair of a subset of DNA double-strand breaks. Patients with ARTEMIS deficiency usually present with severe combined immunodeficiency (SCID) and cellular radiosensitivity, but hypomorphic mutations can cause milder phenotypes (leaky SCID). Objective: We sought to correlate the functional effect of human DCLRE1C mutations on phenotypic presentation in patients with ARTEMIS deficiency. Methods: We studied the recombination and DNA repair activity of 41 human DCLRE1C mutations in Dclre1c(-/-) v-abl kinase-transformed pro-B cells retrovirally engineered with a construct that allows quantification of recombination activity by means of flow cytometry. For assessment of DNA repair efficacy, resolution of gamma H2AX accumulation was studied after ionizing radiation. Results: Low or absent activity was detected for mutations causing a typical SCID phenotype. Most of the patients with leaky SCID were compound heterozygous for 1 loss-of-function and 1 hypomorphic allele, with significant residual levels of recombination and DNA repair activity. Deletions disrupting the C-terminus result in truncated but partially functional proteins and are often associated with leaky SCID. Overexpression of hypomorphic mutants might improve the functional defect. Conclusions: Correlation between the nature and location of DCLRE1C mutations, functional activity, and the clinical phenotype has been observed. Hypomorphic variants that have been reported in the general population can be disease causing if combined in trans with a loss-of-function allele. Therapeutic strategies aimed at inducing overexpression of hypomorphic alleles might be beneficial.en_US
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseases/National Institutes of Health [P01 AI076210-05, R01AI00887]; March of Dimes grant [1-FY13-500]; German Research Foundation [FE 1253/1-1]; Ligue Nationale contre le Cancer (Equipe Labellisee La LIGUE); MZCR [00064203, CZ.2.16/3.1.00/21540]en_US
dc.description.sponsorshipSupported in part by grants P01 AI076210-05 and R01AI00887 from the National Institute of Allergy and Infectious Diseases/National Institutes of Health (to L.D.N.) and March of Dimes grant 1-FY13-500 (to L.D.N.). K.F. received funding from the German Research Foundation (FE 1253/1-1). The JpdeV laboratory is partly funded by Ligue Nationale contre le Cancer (Equipe Labellisee La LIGUE). E.M. is supported by MZCR 00064203 and CZ.2.16/3.1.00/21540.en_US
dc.identifier.doi10.1016/j.jaci.2015.03.005
dc.identifier.endpageU276en_US
dc.identifier.issn0091-6749
dc.identifier.issn1097-6825
dc.identifier.issue1en_US
dc.identifier.pmid25917813en_US
dc.identifier.scopus2-s2.0-84949125497en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage140en_US
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2015.03.005
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12076
dc.identifier.volume136en_US
dc.identifier.wosWOS:000357542200016en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherMosby-Elsevieren_US
dc.relation.ispartofJournal Of Allergy And Clinical Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectV(D)J Recombinationen_US
dc.subjectNonhomologous End-Joiningen_US
dc.subjectDna Repairen_US
dc.subjectArtemis Deficiencyen_US
dc.subjectDclre1c Mutationsen_US
dc.subjectSevere Combined Immunodeficiencyen_US
dc.titleFunctional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiencyen_US
dc.typeArticleen_US

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