| 1. |
- Ekström, Ulf, et al.
(author)
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An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)
- 1999
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In: Clinical Genetics. - : Wiley. - 0009-9163. ; 55:5, s. 332-339
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Journal article (peer-reviewed)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 CHOMldlA7 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.
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| 2. |
- Ekström, Ulf, et al.
(author)
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Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response
- 1998
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972. ; 28:9, s. 740-747
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Journal article (peer-reviewed)abstract
- BACKGROUND: Familial hypercholesterolaemia, an autosomal co-dominant disorder caused by defects in the low-density lipoprotein receptor gene, is strongly associated with premature development of cardiovascular disease. METHODS: In this study, we have applied a gene screening method in a population of familial hypercholesterolaemia patients in order to describe the genetic background of the disease in southern Sweden. These patients were studied with the aim of relating the presence of the different mutations to the clinical expression of the disease and to the response to pharmacological treatment. RESULTS: In 16 out of 21 patients, potentially disease-causing low-density lipoprotein receptor gene defects were found, including five not previously described alterations (C240-->F, C122-->stop, C356-->Y, 785insG, 165delG). No defects in apolipoprotein B were found. One group of patients (n = 4) carried the mutation C122-->stop and another group of patients (n = 4) a mutation causing the substitution W66-->G. Patients in the two genotype subgroups were very similar with respect to lipid levels before treatment. CONCLUSION: A tendency towards differential susceptibility to treatment with statins was observed for the patient groups, encouraging further comparative studies of heterozygous FH patients.
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