title: Human cholesterol 7alpha-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 7alpha-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.
authors.affiliation: Cardiovascular Research Institute, University of California-San Francisco, San Francisco, CA 94143-0130, USA. clivep@itsa.ucsf.edu
authors.forename: Clive R
authors.initials: CR
authors.lastname: Pullinger
authors.forename: Celeste
authors.initials: C
authors.lastname: Eng
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: Sarah
authors.initials: S
authors.lastname: Shefer
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Batta
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Erickson
authors.forename: Andrea
authors.initials: A
authors.lastname: Verhagen
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Rivera
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulvihill
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Malloy
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism; D002769:Cholelithiasis / Q000201:enzymology / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000172:deficiency* / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000201:enzymology / Q000235:genetics; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: D001647:Bile Acids and Salts; D008077:Lipoproteins, LDL; D004247:DNA; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase