IngentaConnect An individual with a healthy phenotype in spite of a pathogenic L...

Authors: Ekström, Ulf¹; Abrahamson, Magnus¹; Florén, Claes-Henrik²; Tollig, Henrik³; Wettrell, Göran⁴; Nilsson, Gerd¹; Sun, Xi-Ming⁵; Soutar, Anne K⁵; Nilsson-Ehle, Peter¹

Source: Clinical Genetics, Volume 55, Number 5, May 1999 , pp. 332-339(8)

Publisher: Blackwell Publishing

Abstract:

Familial hypercholesterolemia (FH) is caused by a defect in the function of the low density lipoprotein (LDL) receptor and inherited in an autosomal, codominant way. In this study we present a 13-year-old girl, compound heterozygote for the LDL receptor mutations C240F and Y167X. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation compared to normal fibroblasts (≪2%, 8%, and ≪2%, respectively). The C240F mutant was expressed in LDL receptor deficient CHOldlA7 cells. Analysis of cell extracts by immunoblotting demonstrated delayed processing of the mutated LDL receptor, which was accumulated as a precursor protein of normal size. A high molecular weight form of the receptor was also detectable in these cells, which probably reflects cross-linking through the unpaired cysteine residue in the binding domain. Cells expressing the C240F mutant protein were unable to mediate uptake and degradation of LDL. The two siblings of the index case also carried the C240F mutation, but surprisingly one of them (a 17-year-old brother) showed no signs of hypercholesterolemia. This observation is consistent with the view that there may be cholesterol lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes.

Keywords: expression; familial hypercholesterolemia; LDL receptor; mutation; phenotype

Document Type: Research article

DOI: 10.1034/j.1399-0004.1999.550506.x

Affiliations: 1: Institute of Laboratory Medicine, Department of Clinical Chemistry, Lund University Hospital, S-221 85 Lund, 2: Department of Internal Medicine, University Hospital of Malmö, S-205 02 Malmö, 3: Department of Pediatrics, Kärnsjukhuset, S-541 85 Skövde, 4: Department of Pediatrics, Lund University Hospital, S-221 85 Lund, Sweden, 5: MRC Lipoprotein Team, Hammersmith Hospital, Ducane Road, London W12 OHS, UK

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An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)