Genetic heterogeneity in familial hypercholesterolemia

evidence for two different mutations affecting functions of low density lipoprotein receptor

J. L. Goldstein, S. E. Dana, G. Y. Brunschede, M. S. Brown

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Abstract

Studies in cultured fibroblasts from patients with the clinical syndrome of homozygous familial hypercholesterolemia have disclosed two different mutations affecting the functions of the low density lipoprotein receptor. One of these mutations, described previously, results in a functionless receptor that does not bind low density lipoproteins. In the cells of six patients who appear to be homozygous for this mutant allele, i.e., receptor negative homozygotes, low density lipoproteins neither suppress hydroxymethylglutaryl CoA reductase (NADPH) [mevalonate:NADP+ oxidoreductase (CoA acylating) EC 1.1.1.34] activity nor stimulate cellular cholesterol esterification, even when examined in the presence of concentrations of lipoprotein 500 times higher than those required to produce maximal biologic effects in normal cells. The second type of mutation, described herein, results in a receptor that has a reduced but not absent function. Fibroblasts from three subjects who possess this mutation, i.e., receptor defective homozygotes, show partial suppression of the same enzyme activity and a detectable increase in cholesterol esterification capacity in the presence of high levels of low density lipoproteins. It was calculated that their degree of function could be achieved if they possessed only about 10% of the normal binding of low density lipoprotein. This level of binding was too low to be reliably detected by the 125I labeled low density lipoprotein binding assay. The finding of a second class of mutant cells in which a defect in low density lipoprotein binding is associated with simultaneous defects in both suppression of hydroxymethylglutaryl CoA reductase activity and stimulation of cholesterol ester formation provides further evidence for the coordinate control of these two processes by the low density lipoprotein receptor.

Original languageEnglish (US)
Pages (from-to)1092-1096
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume72
Issue number3
StatePublished - 1975

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Hyperlipoproteinemia Type II
Genetic Heterogeneity
LDL Receptors
LDL Lipoproteins
Mutation
Hydroxymethylglutaryl CoA Reductases
Esterification
Homozygote
NADP
Fibroblasts
Cholesterol
Mevalonic Acid
Cholesterol Esters
Coenzyme A
Lipoproteins
Oxidoreductases
Alleles
Enzymes

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

@article{e3080364a82e41c082cb4efb057de891,
title = "Genetic heterogeneity in familial hypercholesterolemia: evidence for two different mutations affecting functions of low density lipoprotein receptor",
abstract = "Studies in cultured fibroblasts from patients with the clinical syndrome of homozygous familial hypercholesterolemia have disclosed two different mutations affecting the functions of the low density lipoprotein receptor. One of these mutations, described previously, results in a functionless receptor that does not bind low density lipoproteins. In the cells of six patients who appear to be homozygous for this mutant allele, i.e., receptor negative homozygotes, low density lipoproteins neither suppress hydroxymethylglutaryl CoA reductase (NADPH) [mevalonate:NADP+ oxidoreductase (CoA acylating) EC 1.1.1.34] activity nor stimulate cellular cholesterol esterification, even when examined in the presence of concentrations of lipoprotein 500 times higher than those required to produce maximal biologic effects in normal cells. The second type of mutation, described herein, results in a receptor that has a reduced but not absent function. Fibroblasts from three subjects who possess this mutation, i.e., receptor defective homozygotes, show partial suppression of the same enzyme activity and a detectable increase in cholesterol esterification capacity in the presence of high levels of low density lipoproteins. It was calculated that their degree of function could be achieved if they possessed only about 10{\%} of the normal binding of low density lipoprotein. This level of binding was too low to be reliably detected by the 125I labeled low density lipoprotein binding assay. The finding of a second class of mutant cells in which a defect in low density lipoprotein binding is associated with simultaneous defects in both suppression of hydroxymethylglutaryl CoA reductase activity and stimulation of cholesterol ester formation provides further evidence for the coordinate control of these two processes by the low density lipoprotein receptor.",
author = "Goldstein, {J. L.} and Dana, {S. E.} and Brunschede, {G. Y.} and Brown, {M. S.}",
year = "1975",
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journal = "Proceedings of the National Academy of Sciences of the United States of America",
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T1 - Genetic heterogeneity in familial hypercholesterolemia

T2 - evidence for two different mutations affecting functions of low density lipoprotein receptor

AU - Goldstein, J. L.

AU - Dana, S. E.

AU - Brunschede, G. Y.

AU - Brown, M. S.

PY - 1975

Y1 - 1975

N2 - Studies in cultured fibroblasts from patients with the clinical syndrome of homozygous familial hypercholesterolemia have disclosed two different mutations affecting the functions of the low density lipoprotein receptor. One of these mutations, described previously, results in a functionless receptor that does not bind low density lipoproteins. In the cells of six patients who appear to be homozygous for this mutant allele, i.e., receptor negative homozygotes, low density lipoproteins neither suppress hydroxymethylglutaryl CoA reductase (NADPH) [mevalonate:NADP+ oxidoreductase (CoA acylating) EC 1.1.1.34] activity nor stimulate cellular cholesterol esterification, even when examined in the presence of concentrations of lipoprotein 500 times higher than those required to produce maximal biologic effects in normal cells. The second type of mutation, described herein, results in a receptor that has a reduced but not absent function. Fibroblasts from three subjects who possess this mutation, i.e., receptor defective homozygotes, show partial suppression of the same enzyme activity and a detectable increase in cholesterol esterification capacity in the presence of high levels of low density lipoproteins. It was calculated that their degree of function could be achieved if they possessed only about 10% of the normal binding of low density lipoprotein. This level of binding was too low to be reliably detected by the 125I labeled low density lipoprotein binding assay. The finding of a second class of mutant cells in which a defect in low density lipoprotein binding is associated with simultaneous defects in both suppression of hydroxymethylglutaryl CoA reductase activity and stimulation of cholesterol ester formation provides further evidence for the coordinate control of these two processes by the low density lipoprotein receptor.

AB - Studies in cultured fibroblasts from patients with the clinical syndrome of homozygous familial hypercholesterolemia have disclosed two different mutations affecting the functions of the low density lipoprotein receptor. One of these mutations, described previously, results in a functionless receptor that does not bind low density lipoproteins. In the cells of six patients who appear to be homozygous for this mutant allele, i.e., receptor negative homozygotes, low density lipoproteins neither suppress hydroxymethylglutaryl CoA reductase (NADPH) [mevalonate:NADP+ oxidoreductase (CoA acylating) EC 1.1.1.34] activity nor stimulate cellular cholesterol esterification, even when examined in the presence of concentrations of lipoprotein 500 times higher than those required to produce maximal biologic effects in normal cells. The second type of mutation, described herein, results in a receptor that has a reduced but not absent function. Fibroblasts from three subjects who possess this mutation, i.e., receptor defective homozygotes, show partial suppression of the same enzyme activity and a detectable increase in cholesterol esterification capacity in the presence of high levels of low density lipoproteins. It was calculated that their degree of function could be achieved if they possessed only about 10% of the normal binding of low density lipoprotein. This level of binding was too low to be reliably detected by the 125I labeled low density lipoprotein binding assay. The finding of a second class of mutant cells in which a defect in low density lipoprotein binding is associated with simultaneous defects in both suppression of hydroxymethylglutaryl CoA reductase activity and stimulation of cholesterol ester formation provides further evidence for the coordinate control of these two processes by the low density lipoprotein receptor.

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