Structure and alternative splicing of the rat 7-dehydrocholesterol reductase gene.

The enzyme 7-dehydrocholesterol reductase (Dhcr7) catalyzes the reduction of 7-dehydrocholesterol (DHC), the terminal reaction of the pathway of cholesterol biosynthesis. We report the isolation and characterization of the genomic DNA encoding rat Dhcr7 that contains nine exons and eight introns distributed over 15944 nucleotides (nts) and a consensus GT-AG at each exon/intron junction. Unexpectedly, we have found the occurrence of at least five isoforms of Dhcr7, designated as Dhcr7-AS (alternatively spliced)-1 (1474 nts), -2 (1595 nts), -3 (1602 nts), -4 (1723 nts) and -5 (1287 nts), which was believed to be caused by alternative usage of three 5' noncoding exons. Furthermore, Dhcr7-AS-1 was found to be differentially expressed in six tissues examined while Dhcr7-AS-2 was expressed mainly in liver and brain. Interestingly, human Dhcr7 gene in HepG2 cells produced no detectable isoform while mouse Dhcr7 gene in L929 cells produced three isoforms, suggesting a difference in alternative splicing between species. Thus, regulation of Dhcr7 through the combined mechanisms of tissue-specific transcription and differential alternative splicing appears unique among enzymes characterized from the entire post-lanosterol pathway in cholesterol biosynthesis.

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