A receptor-mediated pathway for cholesterol homeostasis

MS Brown, JL Goldstein - Science, 1986 - science.org
MS Brown, JL Goldstein
Science, 1986science.org
IN 1901, AFTER STUDYING A PATIENT WITH BLACK URINE, A physician named Archibald
Garrod suggested thata single mutant gene can produce a discrete block in a biochemical
pathway, which he called an" inborn error of metabolism." Garrod's brilliant insight
anticipated by40 years the one gene-one enzyme concept of Beadle and Tatum. Similarly,
the chemist Linus Pauling and the physicianVernon Ingram, through study of patients with
sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins …
IN 1901, AFTER STUDYING A PATIENT WITH BLACK URINE, A physician named Archibald Garrod suggested thata single mutant gene can produce a discrete block in a biochemical pathway, which he called an" inborn error of metabolism." Garrod's brilliant insight anticipated by40 years the one gene-one enzyme concept of Beadle and Tatum. Similarly, the chemist Linus Pauling and the physicianVernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1).
We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia (FH). In patients with this disease, the concentration ofcholesterol in the blood is elevated many times above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw lighton fundamental regulatory mechanisms.
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