Density Lipoprotein Receptor Gene Mutations Research Articles

M.597 Characterisation of the low density lipoprotein receptor gene mutations causing familial hyperholesterolaemia in Northwestern Greece

M.597 Characterisation of the low density lipoprotein receptor gene mutations causing familial hyperholesterolaemia in Northwestern Greece

M.597 Characterisation of the low density lipoprotein receptor gene mutations causing familial hyperholesterolaemia in Northwestern Greece

M.597 Characterisation of the low density lipoprotein receptor gene mutations causing familial hyperholesterolaemia in Northwestern Greece

Cholesterol concentrations in cord blood of newborn infants

Familial hypercholesterolemia (FH) is an autosomal dominant disease with an estimated worldwide prevalence of 0.2%. It is caused by a multitude of low density lipoprotein receptor gene mutations. It is characterized with high levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and a high incidence of coronary artery disease in young adults. Cord blood cholesterol concentration is used for mass screening of FH. The purpose of this study was to detect the lipid levels of cord blood in newborn infants from China and to determine the cut-off point after 1 to 2 years follow-up. TC, triglycerides (TG), LDL-C and high density lipoprotein cholesterol (HDL-C) were determined in 242 healthy full-term newborn infants. The mean values of TC, TG, LDL-C and HDL-C in cord blood were (1.69 +/- 0.40) mmol/L, (0.23 +/- 0.12) mmol/L, (0.81 +/- 0.21) mmol/L and (0.58 +/- 0.16) mmol/L (mean +/- standard deviation), respectively. The HDL-C concentration in male neonates was lower than that in female neonates (P < 0.05). After the follow-up of 1 to 2 years for FH, the recommended screening cut-off points were TC > or = 2.47 mmol/L and LDL-C > or = 0.89 mmol/L.

Characterisation of the low density lipoprotein receptor gene mutations causing familial hypercholesterolaemia in Northwestern Greece

Characterisation of the low density lipoprotein receptor gene mutations causing familial hypercholesterolaemia in Northwestern Greece

Functional characterization of two low density lipoprotein receptor gene mutations by fluorescence flow cytometric assessment of receptor activity in stimulated human T-lymphocytes.

We report a functional characterization of the W23X and W66G low density lipoprotein (LDL) receptor gene mutations. The authors used two-color fluorescence flow cytometry to measure LDL receptor activity in stimulated T-lymphocytes, prepared from patients heterozygous for the W23X or W66G mutation, and compared the results with measurements of LDL receptor activity in stimulated T-lymphocytes prepared from unrelated healthy control subjects. It was found that the W23X mutation significantly reduced LDL receptor expression and LDL binding and internalization, and that the W66G mutation significantly reduced LDL receptor expression and LDL binding. LDL internalization in patients heterozygous for the W66G mutation was not significantly reduced. The data support the concepts that the W23X mutation prevents production of LDL receptors (class I) and that the W66G mutation produces LDL receptors unable to recycle normally in cells (class V).

Analysis of low density lipoprotein receptor gene mutations and microsatellite haplotypes in Greek FH heterozygous children: six independent ancestors account for 60% of probands.

This study reports the characterization of 60% of low density lipoprotein receptor (LDLR) gene mutations in 150 unrelated Greek familial hypercholesterolaemia (FH) heterozygous children by the analysis of six LDLR gene mutations. The linkage disequilibrium of two polymorphic microsatellites (D19S394 and D19S221) flanking the LDLR gene on chromosome 19 to the four most common mutations strongly suggests that each mutation is identical-by-descent in the probands included in this study (this is also supported by the geographical distribution of FH families with these mutations throughout Greece) and permits an estimation of the number of generations from a common ancestor for each mutation. The characterization of 60% of LDLR mutations in a representative sample of Greek FH heterozygotes provides a basis for the diagnosis of FH through DNA analysis in Greece, by using single-strand conformation polymorphism analysis followed by allele-specific oligonucleotide hybridization (exon 6 mutations) or restriction endonuclease analysis (C152R, V408M). A rapid diagnostic assay positive for the mutation has been developed for the most common mutation, G528D. The application of simple DNA diagnostic assays for LDLR mutation analysis are appropriate for the early identification of FH heterozygotes in Greece and are useful for the primary prevention of coronary artery disease.

4.P.309 Functional characterization of low density lipoprotein receptor gene mutations in patients with familial hypercholesterolemia

4.P.309 Functional characterization of low density lipoprotein receptor gene mutations in patients with familial hypercholesterolemia

Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations.

We have determined the prevalence of familial hypercholesterolaemia (FH) in a rural Afrikaner community by means of direct DNA screening for three founder-related Afrikaner low density lipoprotein (LDL) receptor gene mutations. A random sample of 1612 persons, aged 15-64 years, was selected as a subsample of 4583 subjects from an Afrikaner community living in the south-western Cape, South Africa. Participants who had a total serum cholesterol (TC) in the high TC category as defined in the consensus recommendations by the Southern African Heart Foundation, were screened for three founder-related LDL receptor gene mutations, causing FH in 90% of Afrikaners. Of the subsample, 201 participants (12.5%) had TC levels above the 80th percentile. In this group the combined prevalence of the three common Afrikaner LDL receptor gene defects (D206E, FH Afrikaner-1; V408M, FH Afrikaner-2; D154N, FH Afrikaner-3) was calculated as 1: 83. When taking into account the reported background prevalence of other FH gene defects of 1:500 in this community, their overall prevalence of FH was estimated to be 1:72. The significant differences found between the FH patients and other high risk patients with raised cholesterol levels were higher TC and LDL cholesterol levels and lower high density lipoprotein cholesterol levels in FH patients. The treatment status of the molecularly identified FH patients and other hypercholesterolaemic persons suggests that this condition is inadequately diagnosed and poorly managed in this study population. An extrapolation to the entire South African population suggests that there are about 112000 FH patients in the country who are under-diagnosed as a group and therefore not receiving the care that would help to reduce the burden of FH-associated ischaemic heart disease in South Africa.

Analysis of low density lipoprotein receptor gene mutations in Belgians with type IIA hyperlipidemia

Analysis of low density lipoprotein receptor gene mutations in Belgians with type IIA hyperlipidemia

Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.

Familial hypercholesterolemia (FH), an autosomal dominant disease caused by mutations in the LDL receptor gene, is five times more frequent in the Afrikaner population of South Africa than it is in the population of the United States and Europe. It has been proposed that the high frequency is due to a founder effect. In this paper, we characterized 24 mutant LDL receptor alleles from 12 Afrikaner individuals homozygous for FH. We identified two mutations that together makeup greater than 95% of the mutant LDL receptor genes represented in our sample. Both mutations were basepair substitutions that result in single-amino acid changes. Each mutation can be detected readily with the polymerase chain reaction and restriction analysis. The finding of two common LDL receptor mutations in the Afrikaner FH homozygotes predicts that these mutations will predominate in the Afrikaner population and that the high frequency of FH is due to a founder effect. The increased incidence of ischemic heart disease in the Afrikaner population may in part be due to the high frequency of these two mutations in the LDL receptor gene.