1/101. Impact of different low-density lipoprotein (LDL) receptor mutations on the ability of LDL to support lymphocyte proliferation.Based on the demand for cholesterol for membrane formation, we determined the ability of low-density lipoprotein (LDL) to support proliferation in lymphocytes bearing different LDL receptor mutations, which were treated "in vitro" with lovastatin to inhibit endogenous cholesterol synthesis. Peripheral lymphocytes were isolated from two patients with homozygous familial hypercholesterolemia (FH), one homozygote for the mutation N804K (FH(Colmenar)) in exon 17, herein described for the first time, and a compound heterozygote carrying the mutations D280G and G528V, which determine a transport-defective biochemical phenotype. Flow cytometric analysis with 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanineperchlorate (Dil)-LDL showed normal LDL binding but defective internalization in lymphocytes from case 1, whereas in lymphocytes from case 2 both LDL binding and internalization were affected. Studies with mitogen-stimulated lymphocytes demonstrated that despite the different phenotype, the ability of LDL to support proliferation was impaired in both cases to a similar extent. These results indicate that internalization of the LDL particle is required for expression of the mitogenic effect of LDL.- - - - - - - - - - ranking = 1keywords = receptor (Clic here for more details about this article) |
2/101. Surgical excision of the tendon xanthoma in familial hypercholesterolemia--a case report.Familial hypercholesterolemia is an autosomal dominant disorder characterized by increased low-density lipoprotein cholesterol, premature atherosclerosis and tendon xanthomas. Genetic studies reveal familial hypercholesterolemia to be a dysfunction of LDL receptor gene on cell surface. Recently various mutations in the LDL receptor gene have been reported. When dna method is not available, the occurrence of tendon xanthomas, an isolated elevation of plasma cholesterol, with a normal concentration of plasma triglycerides virtually establishes the diagnosis of familial hypercholesterolemia. In this report, a 42-year-old male had tendon xanthoma at extensor surface of metacarpophalangeal joint of his right hand, olecranon of the left elbow and both knees, and Achilles tendons. The tendon xanthoma was excised for cosmetic reasons, and the wound healing was slower than average in this case. We suggest that before suture removal, wound healing must be complete. It is important that the hand surgeon recognize that tendon xanthoma is a physical sign of a potentially life-threatening disorder to the patient as well as his family, and that this disorder may respond favorably to early examination and management.- - - - - - - - - - ranking = 0.4keywords = receptor (Clic here for more details about this article) |
3/101. Mutation -59c-->t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia.The low-density lipoprotein receptor (LDLR) plays a major role in cholesterol homeostasis. Mutations in the regulatory region of the LDLR gene, although rare, have been shown to alter transcriptional activity of the gene and can cause familial hypercholesterolaemia (FH). In this study, a transition (c-->t) was identified at nucleotide position -59 within repeat 2 of the LDLR promoter in a South African FH patient of mixed ancestry. By screening 17 family members of the index case for this promoter mutation, two additional single base changes (-124c-->t and-175g-->t) were identified, located at recently described cis- acting regulatory sequences of the LDLR promoter. Both the-59c-->t and the-124c-->t transitions were identified in the normocholesterolaemic son of the index patient. Reporter plasmids containing the normal and mutant promoter fragments were constructed by directional cloning. Transcription studies using a luciferase reporter system demonstrated that the-59c-->t mutation significantly reduces promoter activity in both the presence and absence of sterols ( approximately 40% of normal activity), while the-124c-->t variant increases transcription ( approximately 160%) of the LDLR gene. The intra-familial phenotypic variability observed amongst individuals with the-59c-->t mutation can probably be ascribed to allelic interaction, suggesting that variation in the LDLR promoter region may contribute significantly to the phenotypic expression of FH-related mutations in populations where these mutations prevail.- - - - - - - - - - ranking = 1keywords = receptor (Clic here for more details about this article) |
4/101. Familial hypercholesterolemia. Acceptor splice site (G-->C) mutation in intron 7 of the LDL-R gene: alternate rna editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(honduras-1) [LDL-R1061(-1) G-->C].Familial hypercholesterolemia (FH) is an autosomal dominant lipoprotein disorder caused by defects in the low density lipoprotein (LDL) receptor (R) gene. We report a novel mutation of the LDL-R gene in a 38-year-old man with homozygous FH from the province of Trujilo in Northern honduras. The patient presented with tendinous xanthomas over the extensor tendons as well as xanthelasmas at sites of surgical scars. He was diagnosed with severe coronary artery disease requiring revascularization at age 29. After an unsuccessful course of treatment with simvastatin, the patient has been treated with plasma apheresis and macromolecular plasma filtration bi-monthly. Haplotyping of the LDL-R gene revealed homozygosity for the rare 'J' allele and a loss of the EcoRV restriction cleavage site in exon 8. Single stranded conformational polymorphism of exons 3, 6, 7, 9, 10 and 8 reveals an abnormal migration pattern in exon 8. Direct sequencing of the promoter region, exons 1, 4, 8 and 13 revealed two RFLP's and a novel mutation in intron 7. This mutation consists of G-->C transposition at the acceptor splice site of exon 8 at the last nucleotide of intron 7 [LDL-R1061(-1)G-->C]. Reverse transcriptase (RT) PCR amplification of RNA from monocytes obtained from the patient reveals a decrease in LDL-R mRNA (52% of control) and skipping of exon 8 (approximately 38%, as assessed by densitometric scanning of the amplified fragments) to form a new RNA transcript that includes exons 7 and 9 without frameshift. Alternative rna editing leads to a new cryptic acceptor splice site 17 bp downstream in exon 8 producing a frameshift mutation and a predicted premature stop codon 1138 bp from the transcriptional start site (approxiamtely 62%). Western blotting analysis using a monoclonal antibody (C7) directed at the amino terminus of the LDL-R protein reveals a marked reduction in LDL-R protein expressed in monocytes obtained from the patient. We conclude that LDL-R1061(-1)G-->C is a novel mutation of the LDL-R gene that results in marked decrease in LDL-R mRNA levels and protein expression by two alternate rna editing mechanisms, that cause skipping of exon 8 or the use of a novel cryptic acceptor splice site in exon 8 with a frameshift and premature stop codon. The patient continues to do well on selective plasma filtration but developed bilateral severe carotid artery disease requiring surgical intervention.- - - - - - - - - - ranking = 0.2keywords = receptor (Clic here for more details about this article) |
5/101. Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.Familial hypercholesterolemia (FH) is characterized by a raised concentration of LDL in plasma that results in a significantly increased risk of premature atherosclerosis. In FH, impaired removal of LDL from the circulation results from inherited mutations in the LDL receptor gene or, more rarely, in the gene for apo B, the ligand for the LDL receptor. We have identified two unrelated clinically homozygous FH patients whose cells exhibit no measurable degradation of LDL in culture. Extensive analysis of dna and mRNA revealed no defect in the LDL receptor, and alleles of the LDL receptor or apo B genes do not cosegregate with hypercholesterolemia in these families. FACS((R)) analysis of binding and uptake of fluorescent LDL or anti-LDL receptor antibodies showed that LDL receptors are on the cell surface and bind LDL normally, but fail to be internalized, suggesting that some component of endocytosis through clathrin-coated pits is defective. Internalization of the transferrin receptor occurs normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization signal. Identification of the defective gene will aid genetic diagnosis of other hypercholesterolemic patients and elucidate the mechanism by which LDL receptors are internalized.- - - - - - - - - - ranking = 1.8keywords = receptor (Clic here for more details about this article) |
6/101. Changes in HCV viremia following LDL apheresis in a HCV positive patient with familial hypercholesterolemia.It has been suggested that hepatitis c virus (HCV) can be associated with beta-lipoprotein in human serum. According to this, the LDL receptor could promote endocytosis of such a virus. In the present study, we evaluated the changes in HCV viremia in a HCV positive patient with familial hypercholesterolemia, undergoing both selective (DALI System, Fresenius) and non-selective (plasma exchange) LDL apheresis. HCV-RNA levels did not decrease following selective LDL apheresis, on the contrary showed a random, odd variation pattern (from -35% to 72%). Conversely, plasma exchange steadily induced a drop in HCV viremia (-35/43%), to a lower extent than that of a totally intravascular plasmaprotein, i.e., alpha 2-macroglobulin (-53/54%). These data indicate that beta-lipoprotein may not function as a plasma carrier of HCV, at least in the present case. Moreover, a continuous, quantitatively unforeseeable circulation of HCV virions from the intravascular plasma compartment to other extravascular and intracellular sites, seems to occur during an apheresis session.- - - - - - - - - - ranking = 0.2keywords = receptor (Clic here for more details about this article) |
7/101. Effects of losartan on low-density lipoprotein apheresis.The negative charges of dextran sulfate cellulose (DSC) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by bradykinin production. This study was undertaken to see whether an antagonist of angiotensin receptor (AT1), losartan, could be safely used in a patient treated by DSC-LDL apheresis. losartan (50 mg/day) was given to a patient with coronary heart disease who had been treated by DSC-LDL apheresis and had experienced an anaphylactoid reaction by administration of an angiotensin converting enzyme inhibitor. The effects of losartan on blood pressures and humoral factors were examined by comparing these parameters between apheresis with and without losartan. Blood pressures and plasma levels of bradykinin, renin, and aldosterone were measured before and at 1,000, 2,000, and 3,000 ml of plasma treatment. bradykinin levels during LDL apheresis tended to be higher with losartan than without losartan (without versus with, 529 /- 121 [n = 4, mean /- SE] pg/ml vs. 1,058 /- 49 at the 2,000 ml stage, p < 0.01). The rise of plasma renin activity with losartan (221 /- 26% at the 3,000 ml stage) was significantly greater than that without losartan (144 /- 2.4%). Mean blood pressure decreased by 7% during apheresis with losartan, but blood pressure reduction was not accompanied by any complaints. These results suggest that AT1 receptor antagonists are safely used in patients treated by DSC-LDL apheresis.- - - - - - - - - - ranking = 0.4keywords = receptor (Clic here for more details about this article) |
8/101. testis - a novel storage site in human cholesteryl ester storage disease. autopsy report of an adult case with a long-standing subclinical course complicated by accelerated atherosclerosis and liver carcinoma.A case of long-standing subclinical cholesteryl ester storage disease (CESD) manifesting as hyperlipoproteinaemia type IIb without any hepatomegaly is described. The patient underwent surgical vascular interventions because of accelerated atherosclerosis, which dominated his middle age. CESD was an incidental finding when a liver biopsy specimen was taken because liver malignancy was suspected; the patient's condition proved to be due to a cholangiocarcinoma, which led to his death at the of age 52. The autopsy showed moderate-intensity storage in the set of cells characterized by constitutional high-level receptor-mediated LDL endocytosis (hepatocytes, adrenal cortical cells) and also revealed storage in the leydig cells. The severity with which histiocytes were affected varied regionally, ranging from minimal detectable storage or none at all (gut, lymph nodes, spleen) to extreme lysosomal expansion by cholesteryl ester liquid crystals (bone marrow) or by ceroid (lung, testicular stroma), or by both (liver). The density of the histiocytic population did not correlate with the degree to which parenchymal cells were affected except in the testicular stroma, where it was prominent. The patient was a mixed heterozygote for the G934A and DeltaC(673-5) mutations.- - - - - - - - - - ranking = 0.2keywords = receptor (Clic here for more details about this article) |
9/101. liver transplantation in patients with homozygotic familial hypercholesterolemia previously treated by end-to-side portocaval shunt and ileal bypass.Familial hypercholesterolemia is the result of mutations in the gene that encodes the synthesis of the cellular receptor for low density lipoprotein (LDL). In the homozygous form of the disease (HFHC), cellular LDL receptors either do not form, or, when present, cannot bond LDL and mediate its cellular uptake LDL, and the cholesterol that it transports accumulate in plasma, producing severe premature atherosclerosis and death from coronary artery disease usually before the age of 20. Currently, the only effective treatment is liver transplantation, which, alone or in association with medications, normalizes plasma cholesterol levels. The authors report the cases of 2 siblings with HFHC who underwent portocaval shunt at the ages of 2.5 and 1.5 years, respectively. Portocaval shunt produced an immediate, but insufficient decrease in cholesterol (by 40% and 35%, respectively), leaving them with cholesterol concentrations of about 500 mg/dL. One year later they each underwent ileal bypass without obtaining any significant response. liver transplantation at the ages of 18 and 16 years, respectively, reduced plasma cholesterol concentrations to 129 and 225 mg/dL, respectively. The earlier operations seriously increased the technical difficulty of liver transplantation and did not produce a favorable effect on the natural course of the disease, so portocaval shunt and ileal bypass are not indicated in HFHC, not even for the purpose of delaying liver transplantation.- - - - - - - - - - ranking = 0.4keywords = receptor (Clic here for more details about this article) |
10/101. FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the low density lipoprotein receptor gene in a German patient with homozygous familial hypercholesterolemia.We describe the characterization of a novel mutation in the low density lipoprotein receptor (LDL-R) gene in a patient with true homozygous familial hypercholesterolemia (FH). The combined use of denaturing gradient gel electrophoresis (DGGE) and sequencing of genomic dna revealed a guanine to adenine base substitution at nucleotide position 1013 of the LDL-R cDNA. This point mutation results in a change from cysteine to tyrosine at amino acid residue 317 of repeat A of the epidermal growth factor (EGF) precursor homology domain. Binding, uptake and degradation of iodinated LDL in skin fibroblasts from the homozygous patient were less than 10% of normal. In contrast, binding, uptake and degradation of iodinated VLDL was reduced by only 60, 30, and 38%, respectively. Incubation of the patient's fibroblasts in the presence of cholesterol diminished the residual binding of VLDL by 50%, suggesting that the loss of the highly conserved cysteine at position 317 results in a LDL-R that fails to bind LDL, but retains some ability to bind VLDL by interacting with the apolipoprotein E. Both parents were heterozygous for the C317Y mutation. Interestingly, however, the father presented with markedly elevated levels of triglycerides and VLDL cholesterol, whereas his LDL cholesterol was unexpectedly low. The mother of the index patient had only slightly elevated LDL cholesterol. These observations testify to the biological complexity of genotype-environment interactions in individuals carrying mutations at the LDL-R locus and indicate that genetic analysis importantly complements the clinical and biochemical diagnosis of patients with hyperlipidemia.- - - - - - - - - - ranking = 1keywords = receptor (Clic here for more details about this article) |
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