Alternative titles; symbolsCYTOCHROME P450, SUBFAMILY 46; CYP46CHOLESTEROL 24-HYDROXYLASEHGNC Approved Gene Symbol: CYP46A1Cytogenetic location: 14q32.2 Geno...
Alternative titles; symbols
HGNC Approved Gene Symbol: CYP46A1
Cytogenetic location: 14q32.2 Genomic coordinates (GRCh38): 14:99,684,261-99,727,320 (from NCBI)
▼ Cloning and Expression
Lund et al. (1999) used expression cloning to isolate cDNAs that encode murine and human cholesterol 24-hydroxylases. DNA sequence analysis indicated that both proteins are localized to the endoplasmic reticulum, share 95% identity, and represent a new cytochrome P450 subfamily (CYP46). Both human and mouse proteins contain 500 amino acids. Positions of the introns relative to the predicted amino acid sequence of the proteins were exactly the same in mouse and human. RNA and protein blotting showed that cholesterol 24-hydroxylase is expressed predominantly in the brain. The unique and conserved features of the enzyme implied that it plays important roles in brain cholesterol metabolism.
▼ Gene Structure
Lund et al. (1999) determined that the cholesterol 24-hydroxylase gene contains 15 exons.
By fluorescence in situ hybridization and radiation hybrid analysis, Lund et al. (1999) mapped the human CYP46 gene to chromosome 14q32.1.
▼ Gene Function
The turnover of cholesterol in the brain is thought to occur via conversion of excess cholesterol into 24S-hydroxycholesterol, an oxysterol that is readily secreted from the central nervous system into the plasma. When Lund et al. (1999) transfected CYP46 cDNAs into cultured cells, they found that the cDNAs produced an enzymatic activity that converted cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol.
▼ Molecular Genetics
In 2 groups of patients with Alzheimer disease (AD; 104300), comprising a total of 201 patients, Papassotiropoulos et al. (2003) found that the frequency of a CYP46 T-C polymorphism located 151 bases 5-prime to exon 3, CYP46TT, was associated with increased risk of AD (odds ratio (OR) = 2.16). The OR for APOE4 (107741) allele carriers was 4.38. The OR for the presence of both CYP46TT and APOE4 was 9.63, suggesting a synergistic effect of the 2 genotypes. Neuropathologic examination of AD patients and controls showed that brain beta-amyloid load, CSF levels of soluble beta-amyloid-42, and CSF levels of phosphorylated tau were significantly higher in subjects with the CYP46*TT genotype. Papassotiropoulos et al. (2003) suggested that functional alterations of cholesterol 24-hydroxylase may modulate cholesterol concentrations in vulnerable neurons, thereby affecting changes in amyloid precursor protein processing and beta-amyloid production leading to the development of AD. See also Wolozin (2003).
▼ Animal Model
In Cyp46a1 -/- knockout mice generated by Lund et al. (2003), parameters of hepatic cholesterol and bile acid metabolism remained unchanged compared to wildtype controls, but synthesis of new cholesterol in the brain was reduced by about 40%, despite steady state levels of cholesterol being similar in the knockout mice. These data suggested that the synthesis of new cholesterol and the secretion of 24(S)-hydroxycholesterol are closely coupled and that at least 40% of cholesterol turnover in the brain is dependent on the action of cholesterol 24-hydroxylase.