Abstract 14137: A Newly Identified Case of Apolipoprotein C-II Deficiency Associated with Reduced Transcriptional Activity
Apolipoprotein C-II (Apo C-II) deficiency, which is inherited as an autosomal recessive trait, results in a defective function of lipoprotein lipase and is characterized by marked hypertriglyceridemia. Some cases of apo C-II deficiency were associated with severe atherosclerosis and there was a report showing that apo C-II co-localized with macrophages in the atherosclerotic lesions obtained from LDL receptor-deficient mice. In this study, we have identified a case of apo C-II deficiency associated with a novel mechanism. The proband is a 47-year-old male of Japanese descent suffering from recurrent episodes of acute pancreatitis. His fasting plasma triglyceride (TG) concentrations were over 1000 mg/dl and mild insulin resistance was evident. Although his plasma apo C-II levels were unmeasurable by immunodifusion assay, trace amounts of apo C-II protein was obvious by immunoblot and it's concentration was estimated to be 0.6 mg/dl (normal range:1.5-4.5). Isoelectric focusing and two dimensional gel electrophoresis of the TG-rich lipoproteins revealed that isoelectric point and molecular weight of patient's apo C-II protein isoforms were identical to those of the normal subject, indicating that amino acid structure of the protein was intact. In spite of extensive sequencing, we could find no mutation on the apo C-II gene nor in it's promoter region except for some known SNPs. Southern blot analysis excluded the possibility of major gene rearrangement. We found patient's apo C-II mRNA levels from peripheral blood monocyte-derived macrophages were reduced to the half of normal subject, while expressions of other apoE/C-I/C-IV/C-II gene cluster mRNA remained unchanged. Liver × receptor agonist induction and the size of apo C-II mRNA was identical to those of normal subject. The stability of apoC-II mRNA was not altered. We then analyzed the effects of the SNPs found in his apo C-II promoter/enhancer region using a reporter gene assay. The construct carrying the patient's SNPs resulted in a significantly reduced reporter activity compared with the wildtype DNA fragment. These results suggest that those SNPs are responsible for the low apo C-II mRNA levels in the proband and give us an insight into transcriptional regulation of the apo C-II gene.
- © 2010 by American Heart Association, Inc.