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Low serum high density lipoproteins and a biochemical defect in the cellular efflux of lipids to high density lipoproteins are two common causes of Tangier disease. We're here to tell you more about the human ABC1 gene's construction and the finding of a mutation in the ABC1 gene from the original Tangier disease kindred. The human ABC1 gene's organization is similar to that of the mouse ABC1 gene and other closely related ABC genes. In summary, we report on the human ABC1 gene's genetic organization and find a frameshift mutation in the index case of Tangier disease's ABC1 gene. These findings will be useful in the future characterization of the ABC1 gene's structure and function, as well as the identification of additional ABC1 mutations in patients with Tangier disease patients.
Source link: https://doi.org/10.1073/pnas.96.22.12685
In tissue culture experiments, the interaction of human high density lipoproteins with isolated monocytes from control and Tangier patients was investigated. The cellular association of Tangier monocytes with normal HDL was markedly different from control monocytes. In Tangier monocytes, HDL binding to Tangier monocytes was moderately elevated, and cell-associated HDL radioactivity was 6- to 10-fold elevated. Tangier disease may be a manifestation of intracellular membrane traffic in which HDL is diverted into the lysosomal compartment and degraded instead of being revealed by its normal transcellular route.
Source link: https://doi.org/10.1073/pnas.82.18.6305
The apolipoproteins apo-I and apoA-III in patients with Tangier disease are between 1% and 7% of those in normal patients, respectively. According to increased fractional catabolism in a relatively normal apoA-I and apoA-II synthesis, the low plasma concentrations of apoA-I and apoA-II are due to increased fractional catabolism. Plasma apoA-I and apoA-III were isolated to electrophoretic homogeneity from delipidated plasma lipoproteins from a patient with Tangier disease. However, ApoA-II Tangier's results seemed to be identical to normal apoA-III in amino acid composition and immunological as well as chemical characteristics. These results have been reported as indicating that apoA-I Tangier has a different covalent structure than does normal apoA-I, and that apoA-II Tangier has similar appearance to standard apoA-II.
Source link: https://doi.org/10.1073/pnas.79.8.2485
In comparison to normal serum, in which isoprotein 4 is the most common species [79+/-1. 8 percent], the Tangier serum contained less total apo A-I and isoprotein 2 and 4 were present in roughly equal amounts. The Tangier isoprotein 4 had the same amino-terminal sequence as normal circulating plasma apo A-I. In recombination experiments, it was found that its relationship with normal HDL was similar to the association of normal apo A-I with HDL. These findings reveal that the underlying cause of Tangier disease may be a defective conversion of pro-apo A-I to mature apo A-I, either as a result of a specific structural defect in Tangier, A-I. The inability of Tangier pro-apo A-I to contact with HDL may have been at least partially responsible for the HDL deficiency in Tangier populations.
Source link: https://doi.org/10.1073/pnas.80.19.6081
We discuss two novel coding mutations in the ABCA1 gene that result in premature truncation of the protein, as well as a novel intronic variant that results in the creation of a cryptic splice site acceptor, resulting in premature mRNA splicing and premature truncation of the protein. We also show that this mutation resulted de novo in the proband, marking the first demonstration of a pathogenic de novo mutation in ABCA1 associated with Tangier disease.
Source link: https://doi.org/10.1161/atvb.34.suppl_1.620
No cholesterol efflux was found in apolipoprotein A-I and decreased efflux to HDL 3 in TD-IPSDM and HMDM. In TD-IPSDM and HMDM in the absence of functional ABCA1, treatment of TD cells with LXR agonists, which upregulate ABCA1 expression, failed to raise cholesterol level to apoA-I. The heterozygote ABCA1 mutation carrier in both IPSDM and HMDM had an intermediate defect in cholesterol absorption as well as a partial reaction to the LXR agonist, which was consistent with the presence of one functional allele. On acetylated-LDL loadings, the latter showed a higher cholesterol ester/total cholesterol ratio, according to a control-IPSDM consultant. TD-IPSDM demonstrated enhanced phagocytosis of zymosan particles and enhanced immune response to ATP therapy in lipopolysaccharide-primed IPSDM, but not TNF-alpha.
Source link: https://doi.org/10.1161/atvb.34.suppl_1.190
Aim: The ATP-binding cassette transporter 1 is a membrane protein that is widely used in cholesterol absorption and HDL formation. Specifically, we hypothesized that we might detect distinct protein signatures in the plasma of Tangier patients that correspond to pathways involved in diabetes and inflammation. Methods: We used SOMAscanu00ae equipment to analyze plasma obtained from 5 Tangier disease patients and 7 normolipidemic controls. Using a nonparametric method, we looked for differences in the concentrations of about 1,000 plasma proteins. Proteins related to diabetes and inflammation pathways were significantly more likely to be differentially abundant in the plasma, according to Ingenuity Canonical Pathway's review to see if proteins related to diabetes and inflammation pathways were significantly more likely to be differentially abundant in the plasma. Results: We discovered an enrichment in differentially abundant proteins involved in type II diabetes mellitus signaling and inflammatory pathways, such as granulocyte adhesion and diapedesis.
Source link: https://doi.org/10.1161/atvb.36.suppl_1.392
Abstract u2014Cholesterol efflux is a fundamental process that helps to reduce cholesterol buildup and macrophage foam cell formation. Last week, we reported that cholesterol absorption to high density lipoprotein subfraction 3 was reduced by interferon-u03b3 by a factor of an increase in acyl coenzyme A:cholesterol acyltransferase expression. However, treatment of murine peritoneal macrophages with IFN-u03b3 resulted in a two-fold decrease in HDL-mediated cholesterol secretophagemia, efflux, and lipid-free apolipoprotein A-I was reduced > 4-fold and to basal levels, according to the present study. Downregulation of ABC1 expression by IFN-u03b3 resulted in reduced phosphatidylcholine and sphingomyelin efflux in Tangier fibroblasts, which was consistent with the decrease in cholesterol and phospholipid efflux in Tangier fibroblasts. Although foam cells contained a threefold rise in ABC1 mRNA, a decrease in ABC1 message levels by IFN-u03b3 was observed in foam cells and control macrophages, whereas foam cells had a threefold increase in ABC1 mRNA.
Source link: https://doi.org/10.1161/01.atv.20.6.1565
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