A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus
A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus
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DOI：
10.1007/s00109-007-0199-9
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发表时间：
2007-05-01
影响因子：
4.7
通讯作者：
Hubner, Norbert
中科院分区：
文献类型：
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作者：
Lee-Kirsch, Min Ae;Chowdhury, Dipanjan;Hubner, Norbert
我们最近描述了一种新的常染色体显性遗传性皮肤病，称为家族性冻疮狼疮，并将其遗传位点定位在染色体3p21上。家族性冻疮狼疮表现为儿童早期溃疡性肢端皮肤病变，与关节痛和循环抗核抗体有关。在这项研究中，我们报道了在冻疮红斑狼疮家族的受影响个体中，TREX1编码3 ‘-5 ’修复外切酶1的杂合错义突变（D18N）的鉴定。同源二聚体TREX1是哺乳动物细胞内最丰富的dna酶。我们最近发现TREX1在杀伤淋巴细胞蛋白酶颗粒酶a诱导的凋亡单链DNA损伤中起作用。D18N影响一个高度保守的氨基酸残基，对催化活性至关重要。重组突变型TREX1同型二聚体酶活性不强，而野生型/突变型异源二聚体显示剩余的外核溶解活性，表明杂合功能丧失。携带D18N突变的淋巴母细胞样细胞对颗粒酶a介导的细胞死亡明显不敏感，这表明这种不依赖caspase的细胞凋亡形式在家族性冻疮狼疮的发病机制中起着新的作用。我们的发现也为进一步研究TREX1在常见红斑狼疮中的作用提供了依据。
We recently described a novel autosomal-dominant genodermatosis, termed familial chilblain lupus, and mapped its genetic locus to chromosome 3p21. Familial chilblain lupus manifests in early childhood with ulcerating acral skin lesions and is associated with arthralgias and circulating antinuclear antibodies. In this study, we report the identification of a heterozygous missense mutation (D18N) in TREX1 encoding the 3 '-5 ' repair exonuclease 1 in affected individuals of the family with chilblain lupus. The homodimeric TREX1 is the most abundant intracellular DNase in mammalian cells. We have recently shown that TREX1 plays a role in apoptotic single-stranded DNA damage induced by the killer lymphocyte protease granzyme A. D18N affects a highly conserved amino acid residue critical for catalytic activity. Recombinant mutant TREX1 homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting a heterozygous loss of function. Lymphoblastoid cells carrying the D18N mutation are significantly less sensitive to granzyme A-mediated cell death, suggesting a novel role for this caspase-independent form of apoptosis in the pathogenesis of familial chilblain lupus. Our findings also warrant further investigation of TREX1 in common forms of lupus erythematosus.