Sorting an LDL receptor with bound PCSK9 to intracellular degradation.

Objective: This article reviews the mechanism by which the low density lipoprotein receptor (LDLR) that has bound proprotein convertase subtilisin/kexin type 9 (PCSK9), is rerouted to intracellular degradation instead of being recycled.

Methods: A search of relevant published literature has been conducted.

Results: PCSK9 binds to the LDLR at the cell surface.

PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL receptor (LDLR) at the cell surface and reroutes the internalized LDLR to intracellular degradation. In this study, we have shown that PCSK9-mediated degradation of the full-length 160 kDa LDLR generates a 17 kDa C-terminal LDLR fragment. This fragment was not generated from mutant LDLRs resistant to PCSK9-mediated degradation or when degradation was prevented by chemicals such as ammonium chloride or the cysteine cathepsin inhibitor E64d.

Identification of mutations in the apolipoprotein B-100 gene and in the PCSK9 gene as the cause of hypocholesterolemia.

Background: Characterization of the normally occurring mutations as the cause of hypocholesterolemia may increase our understanding of the normal lipid metabolism.

Methods: DNA from 93 unrelated hypocholesterolemic subjects with a mean (+/-SD) value for total serum cholesterol of 3.3 (+/-0.

Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening.

Background: Too few familial hypercholesterolemia (FH) patients are diagnosed. The most cost-effective strategy to diagnose FH is to examine first-degree relatives of already diagnosed patients. This is referred to as cascade genetic screening.

[Lipid profile in children and adolescents with familial hypercholesterolemia].

Background: Previous reported serum lipid levels in children and adolescents with familial hypercholesterolemia are uncertain. Reasons are that the diagnosis may have been uncertain and that the reported lipid levels have been mainly from patients treated at tertiary referral centres.

Material And Methods: The serum lipid levels in 434 children and adolescents (2-18 years) who had undergone molecular genetic testing for familial hypercholesterolemia as part of cascade genetic screening, were measured.

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

A total of 119 different mutations in the low-density lipoprotein-receptor gene have so far been found to cause familial hypercholesterolemia (FH) among Norwegian patients. As of April 2003, 2390 patients from 959 unrelated families were provided with a molecular genetic diagnosis. Of these, 25.

[A family-based strategy for diagnosing familial hypercholesterolemia].

Background: Patients with familial hypercholesterolaemia have increased risk of developing coronary heart disease. The most cost-effective way of diagnosing patients with familial hypercholesterolaemia is to perform genetic testing of close relatives of already diagnosed patients.

Material And Methods: Probands with familial hypercholesterolaemia in whom the underlying mutation in the low-density lipoprotein receptor gene has been identified were informed that close relatives should also be tested.

Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is at a locus for autosomal dominant hypercholesterolemia, and recent data indicate that the PCSK9 gene is involved in cholesterol biosynthesis. Mutations within this gene have previously been found to segregate with hypercholesterolemia. In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded.