Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency.
Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency.
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DOI：
10.1016/j.jaci.2015.03.005
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Notarangelo LD
中科院分区：
文献类型：
--
作者：
Felgentreff K;Lee YN;Frugoni F;Du L;van der Burg M;Giliani S;Tezcan I;Reisli I;Mejstrikova E;de Villartay JP;Sleckman BP;Manis J;Notarangelo LD
The endonuclease ARTEMIS, encoded by the DCLRE1C gene, is a component of the non-homologous end-joining (NHEJ) 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 may cause milder phenotypes (leaky SCID). We sought to correlate the functional impact of human DCLRE1C mutations on phenotypic presentation in patients with ARTEMIS deficiency. We studied 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 flow-cytometry. For assessment of DNA repair efficacy, resolution of γH2AX accumulation was studied after ionizing radiation. Low or absent activity was detected for mutations causing a typical SCID phenotype. Most of leaky SCID patients were compound heterozygous for one loss of function (LOF) and one 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 may improve the functional defect. 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 may be disease-causing if combined in trans with a LOF allele. Therapeutic strategies aimed at inducing overexpression of hypomorphic alleles may be beneficial.
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