Alternative titles; symbols
HGNC Approved Gene Symbol: CYP27A1
SNOMEDCT: 63246000;
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:218,782,147-218,815,293 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | Cerebrotendinous xanthomatosis | 213700 | Autosomal recessive | 3 |
Sterol 27-hydroxylase, a mitochondrial cytochrome P450, together with 2 protein cofactors, adrenodoxin (103260) and adrenodoxin reductase (103270), hydroxylates a variety of sterols at the C27 position. In the bile acid synthesis pathway, sterol 27-hydroxylase catalyzes the first step in the oxidation of the side chain of sterol intermediates (summary by Cali and Russell, 1991).
Cali and Russell (1991) cloned cDNAs for human sterol 27-hydroxylase from a liver cDNA library by cross-hybridization with a previously cloned rabbit cDNA probe. DNA sequence predicted a protein with a 33-amino acid mitochondrial signal sequence followed by a mature protein of 498 amino acids. RNA blotting experiments demonstrated mRNAs of approximately 1.8 to 2.2 kb in liver and fibroblast cells.
Leitersdorf et al. (1993) demonstrated that the CYP27 gene contains 9 exons and 8 introns and encompasses at least 18.6 kb of DNA. The putative promoter region was found to be rich in GC residues and contained potential binding sites for the transcription factor SP1 (189906) and the liver transcription factor LF-B1.
Using the human CYP27 cDNA in a study of a panel of Chinese hamster/human hybrid cell clones, Cali and Russell (1991) assigned the CYP27A1 gene to chromosome 2 and further regionalized it to 2q33-qter by study of hybrid cells containing various parts of chromosome 2. The Cyp27 gene was similarly mapped to chromosome 1 of the mouse.
Shinkyo et al. (2004) compared vitamin D metabolism by recombinant human CYP2R1 (608713) and CYP27A1. A clear difference was observed between CYP2R1 and CYP27A1 in metabolism of vitamin D2: CYP2R1 showed hydroxylase activity at the C25 position, whereas CYP27A1 showed hydroxylase activity at the C24 and C27 positions. CYP2R1 also showed significantly higher affinity and C25 hydroxylation activity toward vitamin D3 than CYP27A1.
Hypercholesterolemia is a risk factor for estrogen receptor (ER; 133430)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Nelson et al. (2013) showed that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and liver X receptor (see LXRA, 602423) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, Nelson et al. (2013) concluded that lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.
In unrelated patients with cerebrotendinous xanthomatosis (CTX; 213700), Cali et al. (1991) identified homozygous mutations in the CYP27A1 gene (606530.0001-606530.0002).
In a 53-year-old man with an unusual CTX phenotype involving no mental retardation but a progressive neuropsychiatric disorder beginning at age 44, Guyant-Marechal et al. (2005) identified compound heterozygous mutations in the CYP27A1 gene (606530.0013-606530.0014).
By targeted disruption, Rosen et al. (1998) generated mice deficient in sterol 27-hydroxylase. They found that mice with disrupted Cyp27 had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (less than 20% of normal), and formation of bile acids from tritium-labeled 7-alpha-hydroxycholesterol was less than 15% of normal. Compensatory upregulation of hepatic cholesterol 7-alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2- to 3-fold increases in mRNA levels, respectively) was found. No CTX-related pathologic abnormalities were observed. In CTX, there was an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of Cyp27 -/- mice, only traces of bile alcohols were found and there was no evidence of cholestanol accumulation. Rosen et al. (1998) concluded that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans, and that their results did not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.
Meir et al. (2002) developed transgenic mice overexpressing human CYP27A1. Transgenic mice showed elevated blood and tissue levels of 27-hydroxycholesterol and reduced blood levels of 24-hydroxycholesterol. There were no gross morphologic differences between the overexpressing mice and their controls. Total cholesterol and triglyceride levels were unaffected, as were serum lathosterol and 7-alpha-hydroxycholesterol levels. Biliary bile acid composition and fecal neutral steroids were slightly affected. Meir et al. (2002) concluded that levels of 27-hydroxycholesterol are not critically important for cholesterol homeostasis in mice.
Cali et al. (1991) identified 2 different homozygous mutations in the CYP27A1 gene in unrelated cases of cerebrotendinous xanthomatosis (CTX; 213700). Both involved single-basepair substitutions that converted arginine codons (CGPy) to cysteine codons (TGPy). One mutation, called by them CTX1, was at codon 446 near the heme ligand, cys444. The second, called CTX2, was at codon 362 in the adrenodoxin binding region.
See 606530.0001 and Cali et al. (1991).
A relatively high prevalence of cerebrotendinous xanthomatosis (CTX; 213700) has been noted in Jews of Moroccan origin. By single-strand conformation polymorphism analysis followed by sequence analysis, Leitersdorf et al. (1993) identified 2 mutations in the CYP27A1 gene in affected members of 4 families. One mutation was deletion of a thymidine in exon 4 that resulted in frameshift and premature termination 35 nucleotides downstream. The other was a G-to-A transition at the 3-prime splice acceptor site of intron 4 (606530.0004). Two patients from 2 families were homozygous for the frameshift. In 4 families that were studied, 1 was homozygous for the splice mutation, 2 were homozygous for the frameshift mutation, and 1 was a genetic compound for the 2 mutations. Only the fourth family was nonconsanguineous.
See 606530.0003 and Leitersdorf et al. (1993).
In 2 Japanese homozygotes, as well as a heterozygous subject, with cerebrotendinous xanthomatosis (213700), Kim et al. (1994) identified a G-to-A transition in the CYP27A1 gene, changing codon 441 from CGG (arg) to CAG (gln).
In a Japanese homozygote with cerebrotendinous xanthomatosis (213700), Kim et al. (1994) demonstrated that the CYP27 gene contained a C-to-T transition that converted codon 441 from CGG (arg) to TGG (trp). Both this and the arg441-to-gln mutation (606530.0005) resulted in a change in the restriction pattern with the enzymes StuI or HpaII.
In a Japanese family with cerebrotendinous xanthomatosis (CTX; 213700), Chen et al. (1997) identified a G-to-A transition in the CYP27A1 gene, resulting in an arg372-to-gln amino acid substitution. The mutation, homozygous in 1 family, was found in compound heterozygous state in a second Japanese family with a G-to-A substitution at amino acid position 441 (arg441 to gln; 606530.0005). The authors stated that Japanese CTX patients accounted for nearly one-third of all CTX patients reported worldwide.
In a 57-year-old Japanese male with cerebrotendinous xanthomatosis (CTX; 213700), Chen et al. (1998) identified a C-to-A transversion in the -2 position of exon 6 of the CYP27A1 gene, leading to an arg-to-ser substitution at codon 362. This mutation, in addition to causing an amino acid substitution, also affected normal splicing of exon 6, causing activation of a cryptic 5-prime splice site 88 bp upstream from the 5-prime end of exon 6.
In a Japanese family with cerebrotendinous xanthomatosis (CTX; 213700), Shiga et al. (1999) found homozygosity for a G-to-A transition at the 5-prime end in intron 7. Sequencing disclosed a direct conjunction of exon 6 and exon 8, i.e., skipping of exon 7.
Toba et al. (2002) described a Japanese patient with cerebrotendinous xanthomatosis (CTX; 213700) who was compound heterozygous for mutations in the CYP27A1 gene: arg441-to-trp (R441W) and arg372-to-gln (R372Q; 606530.0007). The R441W substitution was the result of a C-to-T transition at nucleotide 1441 in exon 8. The patient was a 33-year-old male who had tendon hypertrophy, gait instability, difficulty in swallowing, juvenile cataract, and mental retardation, but not the rapid speech phenomenon. Dysarthria and excessive salivation were unusual features.
In a 49-year-old woman of Portuguese and Cape Verdean descent who presented with elevated cholestanol levels, markedly reduced mitochondrial 27-hydroxylase activity, and altered bile acid composition, Lamon-Fava et al. (2002) found that cerebrotendinous xanthomatosis (CTX; 213700) was associated with compound heterozygosity for a gly112-to-glu (G112E) mutation and a 5-nucleotide deletion in exon 5 (from nucleotides 965 to 969) that resulted in frameshift and insertion of a premature codon at position 296 (606530.0012). The patient had a history of mild intellectual disability and the development of Achilles tendon xanthomas beginning in early adolescence. She had received more than 18 years of treatment with chenodeoxycholic acid, which effectively prevented progression of the disease.
For discussion of the 5-nucleotide deletion in exon 5 (nucleotides 965 to 969) of the CYP27A1 gene, resulting in a frameshift and insertion of a premature codon at position 296, that was found in compound heterozygous state in a patient with cerebrotendinous xanthomatosis by Lamon-Fava et al. (2002), see 606530.0011.
In a 53-year-old man with an unusual cerebrotendinous xanthomatosis phenotype (CTX; 213700), involving xanthomas since adolescence, no mental retardation, and a progressive neuropsychiatric disorder beginning at age 44, Guyant-Marechal et al. (2005) identified compound heterozygous mutations in the CYP17A1 gene: a 1016C-T transition in exon 5 of the CYP27A1 gene, resulting in a thr339-to-met (T339M) substitution on 1 allele, and a 1435C-G transversion in exon 8, resulting in an arg479-to-gly (R479G) substitution on the other allele.
For discussion of the 1435C-G transversion in exon 8 of the CYP27A1 gene, resulting in an arg479-to-gly (R479G) substitution, that was found in compound heterozygous state in a patient with cerebrotendinous xanthomatosis by Guyant-Marechal et al. (2005), see 606530.0013.
Cali, J. J., Hsieh, C.-L., Francke, U., Russell, D. W. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J. Biol. Chem. 266: 7779-7783, 1991. [PubMed: 2019602]
Cali, J. J., Russell, D. W. Characterization of human sterol 27-hydroxylase: a mitochondrial cytochrome P-450 that catalyzes multiple oxidation reactions in bile acid biosynthesis. J. Biol. Chem. 266: 7774-7778, 1991. [PubMed: 1708392]
Chen, W., Kubota, S., Kim, K.-S., Cheng, J., Kuriyama, M., Eggertsen, G., Bjorkhem, I., Seyama, Y. Novel homozygous and compound heterozygous mutations of sterol 27-hydroxylase gene (CYP27) cause cerebrotendinous xanthomatosis in three Japanese patients from two unrelated families. J. Lipid Res. 38: 870-879, 1997. [PubMed: 9186905]
Chen, W., Kubota, S., Ujike, H., Ishihara, T., Seyama, Y. A novel arg362ser mutation in the sterol 27-hydroxylase gene (CYP27): its effects on pre-mRNA splicing and enzyme activity. Biochemistry 37: 15050-15056, 1998. [PubMed: 9790667] [Full Text: https://doi.org/10.1021/bi9807660]
Guyant-Marechal, L., Verrips, A., Girard, C., Wevers, R. A., Zijlstra, F., Sistermans, E., Vera, P., Campion, D., Hannequin, D. Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype. Am. J. Med. Genet. 139A: 114-117, 2005. [PubMed: 16278884] [Full Text: https://doi.org/10.1002/ajmg.a.30797]
Kim, K.-K., Kubota, S., Kuriyama, M., Fujiyama, J., Bjorkhem, I., Eggertsen, G., Seyama, Y. Identification of new mutations in sterol 27-hydroxylase gene in Japanese patients with cerebrotendinous xanthomatosis (CTX). J. Lipid Res. 35: 1031-1039, 1994. [PubMed: 7915755]
Lamon-Fava, S., Schaefer, E. J., Garuti, R., Salen, G., Calandra, S. Two novel mutations in the sterol 27-hydroxylase gene causing cerebrotendinous xanthomatosis. Clin. Genet. 61: 185-191, 2002. [PubMed: 12000359] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.610303.x]
Leitersdorf, E., Reshef, A., Meiner, V., Levitzki, R., Schwartz, S. P., Dann, E. J., Berkman, N., Cali, J. J., Klapholz, L., Berginer, V. M. Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews of Moroccan origin. J. Clin. Invest. 91: 2488-2496, 1993. [PubMed: 8514861] [Full Text: https://doi.org/10.1172/JCI116484]
Meir, K., Kitsberg, D., Alkalay, I., Szafer, F., Rosen, H., Shpitzen, S., Avi, L. B., Staels, B., Fievet, C., Meiner, V., Bjorkhem, I., Leitersdorf, E. Human sterol 27-hydroxylase (CYP27) overexpressor transgenic mouse model: evidence against 27-hydroxycholesterol as a critical regulator of cholesterol homeostasis. J. Biol. Chem. 277: 34036-34041, 2002. [PubMed: 12119285] [Full Text: https://doi.org/10.1074/jbc.M201122200]
Nelson, E. R., Wardell, S. E., Jasper, J. S., Park, S., Suchindran, S., Howe, M. K., Carver, N. J., Pillai, R. V., Sullivan, P. M., Sondhi, V., Umetani, M., Geradts, J., McDonnell, D. P. 27-hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342: 1094-1098, 2013. [PubMed: 24288332] [Full Text: https://doi.org/10.1126/science.1241908]
Rosen, H., Reshef, A., Maeda, N., Lippoldt, A., Shpizen, S., Triger, L., Eggertsen, G., Bjorkhem, I., Leitersdorf, E. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. J. Biol. Chem. 273: 14805-14812, 1998. [PubMed: 9614081] [Full Text: https://doi.org/10.1074/jbc.273.24.14805]
Shiga, K., Fukuyama, R., Kimura, S., Nakajima, K., Fushiki, S. Mutation of the sterol 27-hydroxylase gene (CYP27) results in truncation of mRNA expressed in leucocytes in a Japanese family with cerebrotendinous xanthomatosis. J. Neurol. Neurosurg. Psychiat. 67: 675-677, 1999. [PubMed: 10519880] [Full Text: https://doi.org/10.1136/jnnp.67.5.675]
Shinkyo, R., Sakaki, T., Kamakura, M., Ohta, M., Inouye, K. Metabolism of vitamin D by human microsomal CYP2R1. Biochem. Biophys. Res. Commun. 324: 451-457, 2004. [PubMed: 15465040] [Full Text: https://doi.org/10.1016/j.bbrc.2004.09.073]
Toba, H., Fukuyama, R., Sasaki, M., Shiga, K., Ishibashi, S., Fushiki, S. A Japanese patient with cerebrotendinous xanthomatosis has different mutations within two functional domains of CYP27. (Letter) Clin. Genet. 61: 77-78, 2002. [PubMed: 11903362] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.610116.x]