The genes coding for apolipoproteins (apo) AI, CIII, and AIV, designated APOA1, APOC3, and APOA4, respectively, are closely linked and tandemly organized in the long arm of the human chromosome 11. A DNA rearrangement involving the genes encoding apoAI and apoCIHl in certain patients with premature atherosclerosis has been associated with deficiency of both apoAI and apoCIll in the plasma of these patients. Structural characterization of the genes for apoAI and apoCIII in one of these patients indicates that this rearrangement consists of a DNA inversion containing portions of the 3' ends of the apoAI and apoCHIl genes, including the DNA region between these genes. The breakpoints of this DNA inversion are located within the fourth exon of the apoAI gene and the first intron of the apoCIHi gene. Thus, this DNA inversion results in reciprocal fusion of the apoAI and apoCIll gene transcriptional units. Expression of these gene fusions in cultured mammalian cells results in stable mRNA transcripts with sequences representing fusions of the apoAI and apoCIl mRNAs. These results indicate that absence of transcripts with correct apoAl and apoCIll mRNA sequences causes apoAI and apoCIII deficiency in the plasma of these patients and suggest that these apolipoproteins are involved in cholesterol homeostasis and protection against premature atherosclerosis. (4,5). A less prominent protein constituent of HDL is apolipoprotein CIII (apoCIII), which is actively exchanged between HDL and triglyceride-rich lipoprotein particles and appears to inhibit both the hydrolysis of these particles by the enzyme lipoprotein lipase and the apolipoprotein E (apoE)-mediated uptake of remnants of these particles by the liver (3).The genes coding for apoAl, apoCIII, and another apolipoprotein, apolipoprotein AIV (apoAIV), are closely linked and tandemly organized in the long arm of human chromosome 11 (6) and are designated APOAI, APOC3, and APOA4, respectively. It has been shown recently that the organization of these genes in the rat is remarkably similar to that in humans, and it was proposed that these genes are similarly organized in the genomes of all mammals (7).Previous studies indicated that an inherited DNA rearrangement involving the genes for apoAl and apoCIII but not the gene for apoAIV in certain patients with premature atherosclerosis is associated with deficiency of apoAI, apo-CIII, and HDL in the plasma of these patients (8-10). This report shows that the DNA rearrangement in the genome of one of these patients is due to inversion of a 6.0-kilobase (kb) DNA segment containing portions of the 3' sequences in the genes for apoAI and apoCIII including the DNA region between these genes. Because of the close physical linkage and convergent transcription of these genes in the normal human genome (6), this DNA inversion results in reciprocal fusion of portions of 5' apoAI with 3' apoCIII and 5' apoCIII with 3' apoAl gene transcriptional units. Expression of these gene fusions in cultured mammalian cells results in mRNAs ...
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