Davies J P, Levy B, Ioannou Y A
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York, 10029, USA.
Genomics. 2000 Apr 15;65(2):137-45. doi: 10.1006/geno.2000.6151.
Niemann-Pick type C1 (NPC1) disease is caused by defects in the NPC1 protein, which result in perturbation of subcellular cholesterol transport. To identify related proteins that may be involved in subcellular cholesterol trafficking, the expressed sequence tag (EST) database was searched to find homologues of human NPC1. A short, weakly similar EST was identified and used to obtain a full-length human cDNA of about 5 kb and two alternatively spliced transcripts. The gene, named NPC1L1, was mapped to chromosome 7p13, contained 20 exons, including an unusually large 1526-bp exon 2, and spanned approximately 29 kb. In contrast to NPC1, the NPC1L1 putative promoter region contained a sterol-regulatory element. The predicted protein shared 42% identity and 51% similarity with NPC1. Interestingly, NPC1L1 contains the conserved amino-terminal "NPC1 domain" and the putative sterol-sensing domain, providing strong evidence that it is related to human NPC1 and suggesting that these may comprise a new family of NPC1-related proteins. However, the two differ with respect to their putative intracellular targeting signals. Collectively, these data suggest that NPC1L1 and NPC1 form part of a family of related proteins that may have similar functions at different subcellular locations, perhaps at sequential steps of the same cholesterol transport pathway.
尼曼-皮克C1型（NPC1）病是由NPC1蛋白缺陷引起的，该缺陷导致亚细胞胆固醇转运紊乱。为了鉴定可能参与亚细胞胆固醇转运的相关蛋白，我们搜索了表达序列标签（EST）数据库以寻找人类NPC1的同源物。我们鉴定出一个短的、相似度较低的EST，并利用它获得了一个约5 kb的全长人类cDNA以及两个可变剪接转录本。该基因被命名为NPC1L1，定位于染色体7p13，包含20个外显子，其中包括一个异常大的1526 bp的外显子2，跨度约为29 kb。与NPC1不同，NPC1L1的推定启动子区域包含一个固醇调节元件。预测的蛋白质与NPC1的同一性为42%，相似性为51%。有趣的是，NPC1L1包含保守的氨基末端“NPC1结构域”和推定的固醇感应结构域，这有力地证明了它与人类NPC1相关，并表明它们可能构成一个新的NPC1相关蛋白家族。然而，两者在推定的细胞内靶向信号方面有所不同。总体而言，这些数据表明NPC1L1和NPC1构成了一个相关蛋白家族的一部分，它们可能在不同的亚细胞位置具有相似的功能，也许在同一胆固醇转运途径的连续步骤中发挥作用。
