Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype

Abstract

Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.

Molecular genetics of atherosclerosis

“…Deletion mutation in CYP7A1 gene that encodes the enzyme cholesterol 7 -hydroxylase has been shown to cause a rare form of hyperlipidemia in homozygous and heterozygous individuals (Pullinger et al 2002). The CC genotype of the A278C polymorphism in the CYP7A1 increases the progression of atherosclerosis (Hofman et al 2005).…”

Genetic analysis of cholesterol gallstone formation: Searching for Lith (gallstone) genes

“…CYP7A1 is an attractive candidate gene because it is the rate-limiting enzyme in the "neutral" pathway for hepatic bile salt biosynthesis and because bile salts are essential for bile formation and for keeping cholesterol molecules solubilized in simple and mixed micelles in bile. Furthermore, Pullinger et al [42] reported a new link between another single gene defect of the CYP7A1 and cholesterol gallstones associated with hypercholesterolemia resistant to HMG-CoA reductase inhibitors in two male homozygotes. Missence mutations in the ATP-binding cassette (ABC) transporter B4 (ABCB4) gene (formerly the multidrug resistance gene 3, MDR3), which encodes for the phosphatidylcholine transporter across the canalicular membrane of the hepatocyte [43,44], are the basis for one particular type of cholelithiasis.…”

Gallenwegserkrankungen jenseits des Säuglingsalters

“…Hohe Prävalenzen finden sich v. a. in Europa, Nord-und Südamerika. Einfluss haben neben der Ernährung auch genetische Faktoren wie zahlreiche LITH-Gene [12]. Die genetische Komponente bei der Entstehung von Gallensteinen beträgt generell 25% [13].…”