Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal
Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal
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DOI：
10.1038/sj.ejhg.5201094
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发表时间：
2004-02-01
影响因子：
5.2
通讯作者：
Lüdecke, HJ
中科院分区：
文献类型：
--
作者：
Kaiser, FJ;Brega, P;Lüdecke, HJ
TRPS1 基因的缺失或突变会导致毛鼻指骨综合征 (TRPS)。该基因编码锌指转录因子，其中包含两个具有碱性氨基酸 LRRRRG (NLS1) 和 RRRTRKR (NLS2) 的区域，类似于潜在的核定位信号 (NLS)。在这里，我们描述了TRPS I型（TRPS I）患者中新型TRPS1突变的鉴定，并通过重建突变TRPS1蛋白和亚细胞定位研究，提供了只有RRRTRKR基序发挥NLS功能的证据。两种不同的突变影响该基序的最后一个精氨酸残基。在两名无关的 TRPS I 患者中发现的精氨酸与组氨酸的交换，以及在另一名无关的患者中发现的精氨酸与半胱氨酸的交换，可防止突变体 TRPS1 在 COS 7 细胞中异位表达时易位至细胞核。相比之下，缺乏保守的 GATA 型锌指结构域和大部分 LRRRRG 基序的突变体能够进入细胞核。
Deletion or mutation of the TRPS1 gene leads to the tricho-rhino-phalangeal syndromes (TRPS). The gene encodes a zinc-finger transcription factor, which contains two regions with basic amino acids LRRRRG (NLS1) and RRRTRKR (NLS2) that resemble potential nuclear localization signals (NLSs). Here, we describe the identification of novel TRPS1 mutations in patients with TRPS type I ( TRPS I) and provide, by reconstructing the mutant TRPS1 proteins and subcellular localization studies, evidence that only the RRRTRKR motif functions as a NLS. Two different mutations affect the last arginine residue of this motif. The exchanges of arginine to histidine, found in two unrelated patients with TRPS I, as well as the exchange of arginine to cysteine, found in another unrelated patient, prevent the translocation of the mutant TRPS1 to the nucleus when ectopically expressed in COS 7 cells. In contrast, a mutant that lacks the conserved GATA-type zinc-finger domain and most of the LRRRRG motif is able to enter the nucleus.