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LDL Receptor Gene (ldl + receptor_gene)
Selected AbstractsThe A370T Variant (StuI Polymorphism) in the LDL Receptor Gene is not Associated with Plasma Lipid Levels or Cardiovascular Risk in UK MenANNALS OF HUMAN GENETICS, Issue 6 2006José Ricardo S. Vieira Summary Over 800 different missense mutations in the low density lipoprotein (LDL) receptor gene (LDLR) have been identified in patients with familial hypercholesterolaemia (FH). Only two of them, including the Alanine to Threonine change at position 370 (A370T), have been discovered in FH patients but do not cause FH. The frequency of the 370T allele has been reported worldwide to be between 0.022 and 0.070, with no clear association with high cholesterol levels or risk for coronary heart disease (CHD) and stroke. To explore this relationship in more detail we have determined this genotype in 2,659 healthy middle-aged (50,61 years) men participating in the prospective Second Northwick Park Heart Study, with 236 CHD and 67 stroke incident events. The genotype distribution was in Hardy-Weinberg equilibrium and in the no-event group the frequency of 370T was 0.046 (95% CI 0.040,0.052). Overall, there was no significant association of the 370T allele with any measured plasma lipid trait, and there was no difference in genotype distribution or allele frequency between the no-event and CHD (0.059; 95% CI 0.040,0.085) or stroke (0.037; 95% CI 0.012,0.085) groups ( p= 0.18 and 0.65, respectively). There was evidence for significant interaction ( p= 0.006) between body mass index (BMI) and genotype on CHD risk, with 370A homozygotes showing the expected higher CHD risk for those with higher BMI, whilst risk for 370T allele carriers was highest in men in the lowest tertile of BMI. The explanation for this association is unclear, and may simply be chance. Thus, these data confirm the absence of a significant impact of the A370T polymorphism on LDL receptor function, at least as measured by the effect on plasma lipid levels and CHD risk. [source] The UMD-LDLR database: additions to the software and 490 new entries to the database,HUMAN MUTATION, Issue 2 2002Ludovic Villéger Abstract Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), one of the most frequent hereditary dominant disorders. The protein defect was identified in 1973, the gene was localized by in situ hybridization in 1985, and since, a growing number of mutations have been reported. The UMD-LDLR database is customized software that has been developed to list all mutations, and also to provide means to analyze them at the nucleotide and protein levels. The database has been recently modified to fulfill the recommendations of the Nomenclature Working Group for human gene mutations. However, in the current version, both the nomenclature and usual LDLR gene mutation names are reported since the latter are more commonly used. The software has also been modified to accommodate the splicing mutations and alleles that carry two nucleotide variations. The current version of UMD-LDLR contains 840 entries, of which 490 are new entries. Point mutations account for 90% of all mutations in the LDLR gene; the remaining are mostly major rearrangements, due to the presence of Alu sequences. Three new routines have been implemented in the software, thus giving users access to 13 sorting tools. In addition to the database, a Web site containing information about polymorphisms, major rearrangements, and promoter mutations is available. Both are accessible to the scientific community (www.umd.necker.fr) and should help groups working on LDLR to check their mutations and identify new ones, and greatly facilitate the understanding of functional classes/genotype relationships and of genotype/phenotype correlations. © 2002 Wiley-Liss, Inc. [source] Cell growth and cholesterol metabolism in human glucose- 6-phosphate dehydrogenase deficient lymphomononuclear cellsCELL PROLIFERATION, Issue 3 2002Batetta B. Atherosclerosis is an inflammatory-fibroproliferative response of the arterial wall involving a complex set of interconnected events where cell proliferation (lymphomonocytes, and endothelial and smooth-muscle cells) and substantial perturbations of intracellular cholesterol metabolism are considered to be among the main features. Glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the hexose-monophosphate shunt pathway, is an essential enzyme involved in both cell growth and cholesterol metabolism, raising the question as to whether G6PD deficiency may have metabolic and growth implications in a deficient population. In the present study, we investigated cell growth and cholesterol metabolism in peripheral blood lymphomononuclear cells (PBMC) from G6PD-normal (n = 5) and -deficient (n = 5) subjects stimulated with lectins (phytohaemoagglutinin and Concanavalin A). G6PD activity, DNA ([3H]-thymidine incorporation) cholesterol synthesis and esterification ([14C]-acetate and [14C]-oleate incorporation), and G6PD, HMGCoA reductase and low density lipoprotein (LDL) receptor mRNA levels (RT-PCR) all increased following lectin stimulation in both normal and G6PD-deficient cells. However, these parameters were significantly lower in G6PD-deficient cells (P < 0.05). It is of interest that G6PD-deficient PBMC, which showed lower expression of G6PD and higher expression of the LDL receptor gene than normal PBMC under basal conditions, exhibited an opposite pattern after stimulation: G6PD and HMGCoA reductase being expressed at significantly higher levels in deficient than in normal cells (P < 0.05). We conclude that the reduced capability of G6PD-deficient cells to respond to mitogenic stimuli and to synthesize cholesterol esters may represent favourable conditions for reducing the risk of cardiovascular diseases. [source] Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicingCLINICAL GENETICS, Issue 6 2008JC Defesche In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3,-splice donor site in exon 4 and R385R was associated with a new 5,-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay. [source] | ||||||||||