A natural hypomorphic variant of the apoptosis regulator Gimap4/IAN1
A natural hypomorphic variant of the apoptosis regulator Gimap4/IAN1
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DOI：
10.4049/jimmunol.179.3.1784
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Butcher, Geoffrey W.
中科院分区：
文献类型：
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作者：
Carter, Christine;Dion, Carine;Butcher, Geoffrey W.
Gimap/Ian家族的GTP酶参与了细胞存活的调节，特别是在淋巴髓样细胞中。对于不同的家庭成员，已经描述了生存和死亡的特性。我们开发了新的血清学试剂来研究死亡前家族成员Gimap4(IAN1)在大鼠体内的表达，该成员在胸腺T细胞阳性选择阶段或之后不久急剧上调。在这些研究中，我们惊讶地发现近交系棕色挪威(BN)大鼠存在Gimap4表达的严重缺陷。遗传分析将这一特征与大鼠4号染色体上的Gimap基因簇联系起来，可能的原因是在BN Gimap4等位基因(AT(+))中插入了AT二核苷酸。该等位基因编码截短形式的Gimap4，与野生型相比缺少21个羧基末端残基。与该等位基因相关的低蛋白表达似乎有转录后原因，因为mRNA表达显然是正常的。体外分析了BN和野生型T细胞的自发和诱导凋亡，并与最近报道的小鼠Gimap4基因敲除进行了比较。这揭示了一种类似于基因敲除的“延迟”的凋亡表型，但没有基因敲除的那么明显。在BN中发现的Gimap4 AT(+)等位基因在近交系大鼠中是罕见的。然而，当研究野生鼠DNA样本时，发现AT(+)等位基因的总频率很高(类似于30%)。这表明该亚型等位基因具有适应性意义。
The Gimap/IAN family of GTPases has been implicated in the regulation of cell survival, particularly in lymphomyeloid cells. Prosurvival and prodeath properties have been described for different family members. We generated novel serological reagents to study the expression in rats of the prodeath family member Gimap4 (IAN1), which is sharply up-regulated at or soon after the stage of T cell-positive selection in the thymus. During these investigations we were surprised to discover a severe deficiency of Gimap4 expression in the inbred Brown Norway (BN) rat. Genetic analysis linked this trait to the Gimap gene cluster on rat chromosome 4, the probable cause being an AT dinucleotide insertion in the BN Gimap4 allele (AT(+)). This allele encodes a truncated form of Gimap4 that is missing 21 carboxyl-terminal residues relative to wild type. The low protein expression associated with this allele appears to have a posttranscriptional cause, because mRNA expression was apparently normal. Spontaneous and induced apoptosis of BN and wild-type T cells was analyzed in vitro and compared with the recently described mouse Gimap4 knockout. This revealed a "delayed" apoptosis phenotype similar to but less marked than that of the knockout. The Gimap4 AT(+) allele found in BN was shown to be rare in inbred rat strains. Nevertheless, when wild rat DNA samples were studied the AT(+) allele was found at a high overall frequency (similar to 30%). This suggests an adaptive significance for this hypomorphic allele.