基因
生物
分子生物学
外显子
管家基因
发起人
结构基因
点突变
调节顺序
基因表达
遗传学
突变
突变体
作者
Zhifang Zhang,Daniel J. Kelly,Jung-Ja P. Kim,Yeqing Zhou,Moira L. Ogden,Alison J. Whelan,Arnold W. Strauss
出处
期刊:Biochemistry
[American Chemical Society]
日期:1992-01-14
卷期号:31 (1): 81-89
被引量:54
摘要
Medium-chain acyl-CoA dehydrogenase (MCAD) is a highly regulated mitochondrial flavo-enzyme that catalyzes the initial reaction in fatty acid beta-oxidation. Deficiency of MCAD is a common inherited defect in energy metabolism. We have previously shown that the mRNA encoding MCAD in an MCAD-deficient child is homozygous for the point mutation A985 to G [Kelly et al. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 9236-9420]. To define the molecular basis of MCAD deficiency and as an initial step in the study of the regulation of MCAD gene expression, we determined the structure and organization of the human MCAD gene. The gene is comprised of 12 exons which span 44 kb of DNA. Comparison of the MCAD gene to MCAD mRNAs from the MCAD-deficient child revealed that missplicing was common, resulting in a variety of exon deletions and intron insertions. The MCAD gene promoter region is extremely GC-rich and lacks prototypical TATA and CAAT boxes. Several regions upstream of the promoter are homologous with mitochondrial enhancers purportedly involved in coordinate expression of nuclear genes encoding mitochondrial proteins. Transfection of chimeric plasmid constructs with 299 bp of upstream sequence into HepG2 cells revealed high-level transcriptional activity. We conclude that the precursor MCAD mRNA is misspliced to a high degree and complexity in association with the G985 mutation and the MCAD gene contains a strong promoter which shares some structural features with other "housekeeping" genes encoding mitochondrial proteins.
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