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

Ekström, Ulf LU ; Abrahamson, Magnus LU ; Florén, Claes-Henrik LU ; Tollig, H; Wettrell, Göran GWE LU ; Nilsson, Gerd LU ; Sun, X M; Soutar, A K and Nilsson-Ehle, Peter LU (1999) In Clinical Genetics 55(5). p.332-339
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
expression, LDL receptor, familial hypercholesterolemia, mutation, phenotype
in
Clinical Genetics
volume
55
issue
5
pages
332 - 339
publisher
Wiley-Blackwell
external identifiers
  • pmid:10422803
  • scopus:0033055179
ISSN
0009-9163
DOI
10.1034/j.1399-0004.1999.550506.x
language
English
LU publication?
yes
id
b197e8ea-b22c-4865-9df8-23397b21935a (old id 1115794)
date added to LUP
2008-07-08 14:30:01
date last changed
2017-01-01 04:54:25
@article{b197e8ea-b22c-4865-9df8-23397b21935a,
  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 (&lt; 2%, 8%, and &lt; 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.},
  author       = {Ekström, Ulf and Abrahamson, Magnus and Florén, Claes-Henrik and Tollig, H and Wettrell, Göran GWE and Nilsson, Gerd and Sun, X M and Soutar, A K and Nilsson-Ehle, Peter},
  issn         = {0009-9163},
  keyword      = {expression,LDL receptor,familial hypercholesterolemia,mutation,phenotype},
  language     = {eng},
  number       = {5},
  pages        = {332--339},
  publisher    = {Wiley-Blackwell},
  series       = {Clinical Genetics},
  title        = {An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)},
  url          = {http://dx.doi.org/10.1034/j.1399-0004.1999.550506.x},
  volume       = {55},
  year         = {1999},
}