Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain
Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain
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DOI：
10.1006/geno.1998.5221
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发表时间：
1998-04-01
期刊：
影响因子：
4.4
通讯作者：
Higgins, MJ
中科院分区：
文献类型：
--
作者：
Cooper, PR;Smilinich, NJ;Higgins, MJ
人类染色体带11p15.5已被证明含有参与几种儿童和成人肿瘤以及Beckwith-Wiedemann综合征（BWS）发展的基因。重叠P1人工染色体克隆从这个地区已被用作模板基因组测序，努力确定这些疾病的候选基因。PowerBLAST从胎脑和肝脏cDNA文库中鉴定出几个与表达序列标签（EST）匹配的序列。北方印迹分析表明，由这些EST鉴定的两个基因编码1-1.5 kb的转录本，主要在胎儿和成人肝脏和肾脏中表达。用RT-PCR和RACE，分离这两个基因的全长转录本，具有编码253和424个氨基酸的推定蛋白质的最大开放阅读框。较大的转录本的预测氨基酸序列的数据库比较表明同源性的膜有机阳离子转运蛋白，因此，我们指定这个基因ORCTL 2（有机阳离子转运蛋白样2）。一个表达的序列多态性提供的证据表明，ORCTL 2基因表现出“泄漏”印迹在人类胎儿肾脏和人类胎儿肝脏。小鼠直系同源（Orctl 2）进行了鉴定，并使用类似的多态性来证明该基因在种间F1小鼠胎肝中的母体特异性表达。较小基因的预测蛋白质在数据库中显示出不显著的相似性。北方和RACE分析表明，该基因可能有多个转录起始位点。对人类基因组结构的测定表明，该转录本的5 '端与ORCTL 2的前两个外显子在不同方向上重叠，这表明一个基因对另一个基因的反义调控可能起作用。因此，我们暂时将第二个转录本命名为ORCTL 2S（ORCTL 2-反义）。这些基因的表达模式和ORCTL 2的印迹表达提示在Wilms瘤（WT）和肝母细胞瘤的发展中可能起作用。尽管对62个WT样本和10个BWS患者的SSCP分析没有鉴定出ORCTL 2或ORCTL 2S中的任何突变，但重要的是检查它们在肿瘤和BWS患者中的表达模式，因为这些基因座的表观遗传改变可能在这些疾病的病因学中起作用。(C)北京：科学出版社.
Human chromosomal band 11p15.5 has been shown to contain genes involved in the development of several pediatric and adult tumors and in Beckwith-Wiedemann syndrome (BWS). Overlapping P1 artificial chromosome clones from this region have been used as templates for genomic sequencing in an effort to identify candidate genes for these disorders. PowerBLAST identified several matches with expressed sequence tags (ESTs) from fetal brain and liver cDNA libraries. Northern blot-analysis indicated that two of the genes identified by these ESTs encode transcripts of 1-1.5 kb with predominant expression in fetal and adult liver and kidney. With RT-PCR and RACE, full-length transcripts were isolated for these two genes, with the largest open reading frames encoding putative proteins of 253 and 424 amino acids. Database comparison of the predicted amino acid sequence of the larger transcript indicated homology to integral membrane organic cation transporters; hence, we designate this gene ORCTL2 (organic cation transporter-like 2). An expressed sequence polymorphism provided evidence that the ORCTL2 gene exhibits "leaky" imprinting in both human fetal kidney and human fetal liver. The mouse orthologue (Orctl2) was identified, and a similar polymorphism was used to demonstrate maternal-specific expression of this gene in fetal liver from interspecific F1 mice. The predicted protein of the smaller gene showed mo significant similarity in the database. Northern and RACE analyses suggest that this gene may have multiple transcription start sites. Determination of the genomic structure in humans indicated that the 5'-end of this transcript overlaps in divergent orientation with the first two exons of ORCTL2, suggesting a possible role for antisense regulation of one gene by the other. We, therefore, provisionally name this second transcript ORCTL2S (ORCTL2-antisense). The expression patterns of these genes and the imprinted expression of ORCTL2 are suggestive of a possible role in the development of Wilms tumor (WT) and hepatoblastoma. Although SSCP analysis of 62 WT samples and 10 BWS patients did not result in the identification of any mutations in ORCTL2 or ORCTL2S, it will be important to examine their expression pattern in tumors and BWS patients, since epigenetic alteration at these loci may play a role in the etiology of these diseases. (C) 1998 Academic Press.