Congenital lipoid adrenal hyperplasia: the human gene knockout for the steroidogenic acute regulatory protein.

Lipoid CAH was first described in detail as an inherited endocrine disorder by Prader and colleagues (Prader & Gurtner 1955, Prader & Siebenmann 1957, Prader & Anders 1962), although at least four autopsy cases appeared earlier in the pathology literature (Tilp 1913, Brutschy 1920, Zahn 1948, Sandison 1955). Prader’s group described male pseudohermaphroditism, an apparent lack of adrenal steroids and accumulation of lipid deposits in the adrenal, inherited in an autosomal recessive fashion. Written in German, Prader’s work was not widely recognized until Camacho et al. (1968) reported an apparently milder case, with the onset of clinically apparent salt loss at 8 months of age, and postulated that the disorder was in one of the enzymes involved in the conversion of cholesterol to pregnenolone. However, the nature of the defect was unclear, in part because the enzymology of the conversion of cholesterol to pregnenolone was unclear. At that time it was thought that the conversion of cholesterol to pregnenolone required at least three enzymes, a 20a-hydroxylase, a 22-hydroxylase, and a 20,22 desmolase (Shimizu et al. 1961), and that lipoid CAH was due to a defect in one of these enzymes. Degenhart et al. (1972) were the first to study lipoid CAH in vitro, by comparing the production of pregnenolone by mitochondria from the adrenals of affected and unaffected infants. Mitochondria from affected tissue could not convert cholesterol to pregnenolone (although normal mitochondria could), but affected mitochondria could convert 20a-hydroxycholesterol to pregnenolone. They logically concluded that the defect was in a specific 20a-hydroxylase; this conclusion was incorrect, but the experimental design was prescient: 23 years later we used a similar experiment to prove that lipoid CAH was due to a mutation in a non-enzymatic protein (Lin et al. 1995). Koizumi et al. (1977) also found that affected mitochondria failed to convert cholesterol to pregnenolone but were unable to account for Degenhart’s findings. By this time it was clear that the conversion of cholesterol to pregnenolone was catalyzed by a mitochondrial cytochrome P450 enzyme, termed P450scc, (where scc denotes side chain cleavage), which functions as the terminal oxidase in a mitochondrial electron-transfer chain where NADPH donated electrons to a flavoprotein (adrenodoxin reductase) which then transferred them to an iron-sulfur protein (adrenodoxin) which in turn donated them to P450scc (Kimura & Suzuki 1965, Omura et al. 1966, Shikita & Hall 1973) (for review see Miller 1988). Thus Koizumi examined the total P450 in the affected adrenal mitochondria in the only fashion then available, by carbon monoxide-induced difference spectra, and concluded that affected mitochondria had roughly half of the normal amount of total cytochrome P450. At that time it was known that steroid 11â-hydroxylase and 18-hydroxylase activities were also catalyzed by a mitochondrial P450, and as the affected mitochondria had normal 11â-/18-hydroxylase activity but failed to convert cholesterol to pregnenolone, Koizumi et al. (1977) logically concluded that the 227