Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome
Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome
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DOI：
10.1073/pnas.0914865107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Yan, Catherine T.
中科院分区：
文献类型：
--
作者：
Rucci, Francesca;Notarangelo, Luigi D.;Yan, Catherine T.
DNA连接酶IV（LIG 4）是非同源末端连接（NHEJ）修复途径的重要组成部分，在V（D）J重组中起关键作用。人类中的亚型LIG 4突变与细胞放射敏感性增加、小头畸形、面部畸形、生长迟缓、发育迟缓和不同程度的免疫缺陷相关。我们已经产生了一个基因敲入小鼠模型与纯合Lig 4 R278 H突变，对应于第一个在人类中报道的LIG 4突变。纯合突变小鼠Lig 4（R278 H/R278 H）（Lig 4（R/R））的表型包括生长迟缓、寿命缩短、对电离辐射的严重细胞敏感性以及T和B细胞发育的非常严重但不完全的阻滞。外周血T淋巴细胞表现出活化和无反应性表型，活力降低，和有限的库，让人联想到人类泄漏的SCID。基因组的不稳定性与胸腺肿瘤的高发生率有关。最后，Lig 4（R/R）小鼠自发产生包括自身反应特异性的低亲和力抗体，但不能产生高亲和力抗体反应。这些发现强调了LIG 4在淋巴细胞发育和功能以及基因组稳定性维持中的重要性，并为人类LIG 4综合征的复杂表型提供了模型。
DNA ligase IV (LIG4) is an essential component of the nonhomologous end-joining (NHEJ) repair pathway and plays a key role in V(D)J recombination. Hypomorphic LIG4 mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency. We have generated a knock-in mouse model with a homozygous Lig4 R278H mutation that corresponds to the first LIG4 mutation reported in humans. The phenotype of homozygous mutant mice Lig4(R278H/R278H) (Lig4(R/R)) includes growth retardation, a decreased life span, a severe cellular sensitivity to ionizing radiation, and a very severe, but incomplete block in T and B cell development. Peripheral T lymphocytes show an activated and anergic phenotype, reduced viability, and a restricted repertoire, reminiscent of human leaky SCID. Genomic instability is associated with a high rate of thymic tumor development. Finally, Lig4(R/R) mice spontaneously produce low-affinity antibodies that include autoreactive specificities, but are unable to mount high-affinity antibody responses. These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans.