Benzow Kellie A, Koob Michael D
Institute of Human Genetics, MMC 206 UMHC, 420 Delaware St. SE., University of Minnesota, Minneapolis, Minnesota 55455, USA.
Mamm Genome. 2002 Mar;13(3):134-41. doi: 10.1007/s00335-001-2105-2.
Spinocerebellar ataxia type 8 (SCA8) is caused by a CTG expansion in an untranslated, endogenous antisense RNA that overlaps the Kelch-like 1 ( KLHL1) gene. The normal function of this transcript is currently unknown. We have now identified the promoter region for the KLHL1-antisense ( KLHL1AS) RNA and report that a Klhl1as transcript is present in the mouse as well. Human and mouse KLHL1AS are transcribed from homologous promoter regions in the first intron of KLHL1 and extend through the transcription and translation start sites as well as the first splice donor sequence of KLHL1. We found that the mouse Klhl1as RNA is not spliced and terminates in a polyadenylation site in the Klhl1 promoter region, whereas both the present and previous work show that human KLHL1AS is highly variably spliced into processed transcripts that contain up to six exons. Mouse Klhl1as transcript was detected in RNA isolated from the cerebellum and from total adult brain and total fetal tissue, and at a low level in testis and ovary. Similarly, human KLHL1AS is expressed in various brain tissues, including the cerebellum, the tissue most affected by SCA8, and was detected at low levels in testis and kidney. The evolutionary conservation of this antisense/sense transcriptional organization strongly indicates that KLHL1AS transcripts play a significant biological role in both human and mouse, presumably as a regulator of KLHL1 expression.
8型脊髓小脑共济失调（SCA8）由一种与kelch样蛋白1（KLHL1）基因重叠的非翻译内源性反义RNA中的CTG扩增引起。该转录本的正常功能目前尚不清楚。我们现已确定了KLHL1反义（KLHL1AS）RNA的启动子区域，并报告小鼠中也存在Klhl1as转录本。人和小鼠的KLHL1AS均从KLHL1第一个内含子中的同源启动子区域转录而来，并延伸至KLHL1的转录和翻译起始位点以及第一个剪接供体序列。我们发现，小鼠Klhl1as RNA不进行剪接，并在Klhl1启动子区域的聚腺苷酸化位点终止，而目前和之前的研究均表明，人KLHL1AS高度可变地剪接成含有多达六个外显子的加工转录本。在从小脑、成年大脑总组织和胎儿总组织中分离的RNA中检测到小鼠Klhl1as转录本，在睾丸和卵巢中检测到的水平较低。同样，人KLHL1AS在包括小脑（受SCA8影响最严重的组织）在内的各种脑组织中表达，在睾丸和肾脏中检测到的水平较低。这种反义/正义转录组织的进化保守性强烈表明，KLHL1AS转录本在人和小鼠中均发挥着重要的生物学作用，可能作为KLHL1表达的调节因子。
