Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV

被引:145
作者
Buck, D
Moshous, D
de Chasseval, R
Ma, YM
le Deist, F
Cavazzana-Calvo, M
Fischer, A
Casanova, JL
Lieber, MR
de Villartay, JP
机构
[1] Hop Necker Enfants Malad, INSERM, U429, Unite Dev Normal & Pathol Syst Immunitaire, F-75015 Paris, France
[2] Univ Paris 05, Fac Med Rene Descartes, F-75005 Paris, France
[3] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA
[4] Hop Necker Enfants Malad, APHP, Dept Biotherapy, Paris, France
[5] Hop Necker Enfants Malad, APHP, Unite Immunol & Hematol, Paris, France
[6] Hop Necker Enfants Malad, INSERM, U550, Lab Genet Humaine Malad Infect, Paris, France
[7] Univ Paris 05, Paris, France
关键词
DNA ligaseIV; DNA repair; immune development; immunodeficiency; V(D)J recombination;
D O I
10.1002/eji.200535401
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
DNA double-strand breaks (dsb) during V(D)J recombination of T and B lymphocyte receptor genes are resolved by the non-homologous DNA end joining pathway (NHEJ) including at least six factors: Ku70, Ku80, DNA-PKcs, Artemis, Xrcc4, and DNA ligase W (Lig4). Artemis and Lig4 are the only known V(D)J/NHEJ factors found deficient in human genetic disorders. Null mutations of the Artemis gene result in a complete absence of T and B lymphocytes and increased cellular sensitivity to ionizing radiations, causing radiosensitive-SCID. Mutations of Lig4 are exclusively hypomorphic and have only been described in six patients, four exhibiting mild immunodeficiency associated with microcephaly and developmental delay, while two patient had leukemia. Here we report a SCID associated with microcephaly caused by compound heterozygous hypomorphic mutations in Lig4. Residual activity of Lig4 in these patients is underscored by a normal pattern of TCR-alpha and -beta junctions in the T cells of the patients and a moderate impairment of V(D)J recombination as tested in vitro. These observations contrast with the severity of the clinical immunodeficiency, suggesting that Lig4 may have additional critical roles in lymphocyte survival beyond V(D)J recombination.
引用
收藏
页码:224 / 235
页数:12
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