Abstract 1921: Clinical Impact of Heterozygous Carrier of Autosomal Recessive Hypercholesterolemia on Asymptomatic Hyperlipidemic Patients: Evidence From Familial Gene Analysis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hayato Tada ◽  
Masa-aki Kawashiri ◽  
Tohru Noguchi ◽  
Chiaki Nakanishi ◽  
Masayuki Tsuchida ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Genetic Defect ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Serum Triglyceride ◽  
Adaptor Protein ◽  
Receptor Internalization ◽  
Single Mutation ◽  
Heterozygous Carrier ◽  
Autosomal Recessive Hypercholesterolemia

Autosomal recessive hypercholesterolemia (ARH) is an extremely rare genetic defect, and is recognized only around 50 cases in all over the world. The genetic cause of ARH is mutation in an adaptor protein involved in low-density lipoprotein (LDL) receptor internalization, which results in marked elevation of serum LDL cholesterol (LDL-C) and premature atherosclerosis. Therefore, few data exist regarding the clinical significance about the heterozygous carrier of ARH. We recently identified the second ARH patient (Ins C 599 ) in Japan and his some relatives who have the same single mutation (heterozygous). We identified 11 heterozygous ARH carriers (male=5, mean age=48.2) and 7 non-carriers (male=3, mean age=53.3) in the same family. In addition, we screened the same mutations in unrelated consecutive 500 hyperlipidemic patients (male=32, mean age=49.4) with mean LDL-C of 225.2±6.1mg/dl using PCR to determine its frequency and examined their clinical features. We identified an unrelated heterozygous ARH carrier and a non-carrier in the same family among unrelated to the original family. Serum LDL-C levels of heterozygous ARH carriers (mean=153.8±35.8mg/dl) were significantly higher than those of non-carriers (mean=108.2±41.4mg/dl, p<0.05). Serum triglyceride (151.9±110.7mg/dl vs 140.4±48.8mg/dl) and high-density lipoprotein cholesterol (57.4±11.0mg/dl vs 54.0±11.9mg/dl) levels were not different between them. Interestingly, heterozygous ARH carriers didn’t show any xanthomas including Achilles tendon (6.4±1.1mm vs 5.7±1.1mm) in contrast to FH, which is frequently associated with typical xanthoma. These results demonstrate that heterozygous ARH (Ins C 599 ) carriers show higher LDL-C levels compared with non-carrier family member without tendon xanthomas observed in FH. We suggest that heterozygous ARH (Ins C 599 ) carrier may explain a part of primary hypercholesterolemia.

scholarly journals The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein

2007 ◽  
Vol 402 (1) ◽  
pp. 17-23 ◽  
Author(s):  
David R. Taylor ◽  
Nigel M. Hooper
Keyword(s):  
Prion Protein ◽  
Low Density Lipoprotein ◽  
Neuronal Cells ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Cellular Prion Protein ◽  
Low Density ◽  
Related Protein ◽  
Density Lipoprotein Receptor

PrPC (cellular prion protein) is located at the surface of neuronal cells in detergent-insoluble lipid rafts, yet is internalized by clathrin-dependent endocytosis. As PrPC is glycosyl-phosphatidylinositol-anchored, it requires a transmembrane adaptor protein to connect it to the clathrin endocytosis machinery. Using receptor-associated protein and small interfering RNA against particular LDL (low-density lipoprotein) family members, in combination with immunofluorescence microscopy and surface biotinylation assays, we show that the transmembrane LRP1 (LDL receptor-related protein 1) is required for the Cu2+-mediated endocytosis of PrPC in neuronal cells. We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrPC.

scholarly journals Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1

2002 ◽  
Vol 110 (11) ◽  
pp. 1695-1702 ◽  
Author(s):  
Emily R. Eden ◽  
Dilipkumar D. Patel ◽  
Xi-Ming Sun ◽  
Jemima J. Burden ◽  
Michael Themis ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Ldl Receptor ◽  
Receptor Function ◽  
Autosomal Recessive Hypercholesterolemia ◽  
In Cells

UNC13D and PRF1 Mutations in Childhood Patients with Hemophagocytic Lymphohistiocytosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1334-1334
Author(s):  
Udo zur Stadt ◽  
Karin Beutel ◽  
Florian Oyen ◽  
A. Sarper Diler ◽  
Hartmut Kabisch ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Autosomal Recessive ◽  
Genetic Defect ◽  
Geographic Origin ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Single Mutation ◽  
Nonsense Mutations ◽  
Coding Regions ◽  
Gene Defects

Abstract Introduction: Familial Hemophagocytic Lymphohistiocytosis (FHLH) is an autosomal recessive disease affecting young children. It manifests itself as a severe hyperinflammatory syndrome with activated macrophages and T-lymphocytes. Mutations in Perforin (PRF1) are responsible for FHL-2 in about 15 to 50 % of the patients. Defective granule exocytosis due to mutations in UNC13D have recently been described as the genetic defect underlying FHL-3. Both types are phenotypically not distinguishable from one another. Patients and Methods: Genetic analysis was performed in either the 2 or the 32 exons of PRF1 and UNC-13D, respectively, in 61 patients with hemophagocytic lymphohistiocytosis (HLH) of different geographic origin (28 from Germany, 24 from Turkey and 9 from other countries). Results: We identified mutations in 28 samples investigated (18 in PRF1, 10 in UNC-13D). Besides several known mutations novel deletions, missense and nonsense mutations were detected in both genes scattering the whole coding regions. The Trp374stop mutation (11/13 patients with a PRF1 mutation from Turkey) was the only single mutation repeatedly observed in several patients with a common geographic origin. In HLH patients from Germany, 7/28 patients showed homozygous or compound heterozygous mutations in either PRF1 (3) or UNC13D (4). In 24 HLH patients from Turkey 13 patients with a mutation in PRF1 and 4 patients with a mutation in UNC13D were identified. In addition, four out of 9 patients with a different geographic origin showed mutations in one of this genes. In 10 patients only one heterozygous mutation in UNC13D was detected so far. In these cases, control samples or regulatory regions of the gene have to be analysed to ascertain the relevance of the underlying mutation. Defect Turkey German Other All UNC13D 4 4 2 10 PRF1 13 3 2 18 Unknown 7 21 5 33 Discussion: Overall, UNC-13D and PRF1 mutations were detectable in 45% of the cases. Our results indicate that FHL-2 and FHL-3 account for more than 60% of the HLH cases of Turkish origin with only a small number involving UNC-13D. In contrast, gene defects were identified in only 25% of the patients with a German ancestry. This work was supported by the Foerdergemeinschaft Kinderkrebszentrum Hamburg e. V.

scholarly journals Fluorescent low density lipoprotein for observation of dynamics of individual receptor complexes on cultured human fibroblasts.

1981 ◽  
Vol 90 (3) ◽  
pp. 595-604 ◽  
Author(s):  
L S Barak ◽  
W W Webb
Keyword(s):  
Low Density Lipoprotein ◽  
Human Fibroblasts ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Internalization ◽  
Low Density ◽  
Receptor Complexes ◽  
Heparin Sulfate ◽  
Cultured Human Fibroblasts ◽  
Coa Reductase

The visible wavelength excited fluorophore 3,3'-dioctadecylindocarbocyanine iodide (Dil[3]) was incorporated into human low density lipoprotein (LDL) to form the highly fluorescent LDL derivative dil(3)-LDL. Dil(3)-LDL binds to normal human fibroblasts and to human fibroblasts defective in LDL receptor internalization but does not bind to LDL receptor-negative human fibroblasts at 4 degrees C or 37 degrees C. It is internalized rapidly at 37 degrees C by normal fibroblasts and depresses the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) in a manner similar to that of LDL. It is prevented from binding to the LDL receptor by an excess of unlabeled LDL or by heparin sulfate. Identical distributions of dil(3)-LDL are observed on cells by either indirect immunofluorescence with fluorescein-labeled antibody or directly by dil(3) fluorescence. Upwards of 45 molecules of dil(3) are incorporated per molecule of LDL without affecting binding to the receptor. This labeling renders individual molecules visible by their fluorescence and enables the derivative to be used in dynamic studies of LDL-receptor motion on living fibroblasts by standard fluorescence techniques at low LDL receptor density. Observations with this derivative indicate that the LDL-receptor complex is immobilized on the surface of human fibroblasts but, when free of this linkage, undergoes a Brownian motion consistent with theory.

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