Homozygous familial hypercholesterolemia: specificity of the biochemical defect in cultured cells and feasibility of prenatal detection

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19 Scopus citations


The regulation of the activity of 3 hydroxy 3 methylglutaryl Coenzyme A reductase (HMG CoA reductase), the rate controlling enzyme in cholesterol biosynthesis, is defective in subjects with the homozygous form of familial hypercholesterolemia. Using cultured skin fibroblasts as an available source of this enzyme, its activity has been compared in cells from eight normal controls, five homozygotes affected with familial hypercholesterolemia, eight heterozygotes with familial hypercholesterolemia, and four individuals with forms of hyperlipidemia other than familial hypercholesterolemia. In fibroblasts grown in fetal calf serum containing lipoproteins, HMG CoA reductase activity was low in normal controls (mean ± SEM, 4.9 ± 0.9 pmoles/min per milligram protein) and in hyperlipidemic controls (3.8 ± 1.0), significantly higher to differences heterozygotes (12.5 ± 3.8, P < .01), and markedly higher in homozygotes (95.4 ± 23.9,P <.001). In cells switched from growth medium containing fetal calf serum to medium containing serum deficient in lipoproteins, enzyme specific activity rose on the average 16 fold in normal controls (range, 6.1-41.6), 23 fold in hyperlipidemic controls (range, 15.9-42.4), 12 fold that heterozygotes (range, 5.6-28.9), but less than 1.6 fold in homozygotes (range 0.95-2.3). Thus, the nearly complete defect in the regulation of HMG CoA reductase activity by lipoproteins in fibroblasts from homozygotes with familial hypercholesterolemia appears to be a specific genetic marker for this inherited disorder. The fact that cultured fibroblasts derived from normal amniotic fluid showed a level and a pattern of regulation of HMG CoA reductase activity quantitatively and qualitatively similar to hat of both normal controls and heterozygotes suggests that prenatal detection of the homozygote with familial hypercholesterolemia is technically feasible.

Original languageEnglish (US)
Pages (from-to)199-206
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Dec 1 1974

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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