title: Adrenocortical lipid depletion gene (ald) in AKR mice is associated with an acyl-CoA:cholesterol acyltransferase (ACAT) mutation.
abstract: ald, a recessive allele in AKR inbred mice, is responsible for complete adrenocortical lipid depletion in postpubertal males, which appears to be androgen dependent. Two recent observations (adrenocortical lipid depletion in acyl-CoA:cholesterol acyltransferase-deficient (Acact-/-) mice and the mapping of Acact to a region of chromosome 1 containing the ald locus) prompted us to ask whether adrenocortical lipid depletion in AKR mice results from an Acact mutation. Refined genetic mapping of Acact and ald was consistent with colocalization of these loci. Crossing Acact-/- with AKR (ald/ald) mice yielded postpubertal male offspring characterized by adrenocortical lipid depletion, indicating that these loci are not complementational and are therefore allelic. Immunoblotting of preputial gland homogenates demonstrated that AKR mice had an ACAT protein with a lower molecular mass than other mouse strains. Analysis of Acact cDNA from AKR mice revealed a deletion of the first coding exon and two missense mutations. Despite these coding sequence differences, the ACAT protein from the ald allele catalyzed cholesterol esterification activity at levels similar to that of wild-type protein. We speculate that the adrenocortical lipid depletion resulting from the ald mutation is caused by an altered susceptibility of the mutant protein to modifying factors, such as androgen production at puberty, in an as yet undetermined manner.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94141-9100, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Meiner
authors.forename: C L
authors.initials: CL
authors.lastname: Welch
authors.forename: S
authors.initials: S
authors.lastname: Cases
authors.forename: H M
authors.initials: HM
authors.lastname: Myers
authors.forename: E
authors.initials: E
authors.lastname: Sande
authors.forename: A J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: R V
authors.initials: RV
authors.lastname: Farese
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D000818:Animals; D002874:Chromosome Mapping; D005260:Female; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D002785:Sterol O-Acyltransferase / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase