Alternative titles; symbols
HGNC Approved Gene Symbol: CYP26A1
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:93,073,475-93,077,885 (from NCBI)
Retinoic acid (RA) plays an important role in regulating gene expression during embryonic development and in the maintenance of adult epithelial tissues. Cytochrome P450 retinoic acid-metabolizing enzyme, designated P450RAI by White et al. (1997), metabolizes retinoic acid into several forms, thereby inactivating it. P450RAI is a member of the CYP26 class of cytochromes P450 (see 122720), which was first identified in zebrafish.
White et al. (1997) cloned the P450RAI gene from human retinoic acid-treated teratocarcinoma cells using the zebrafish gene as a probe. The predicted 497-amino acid human protein has 68% amino acid identity to the zebrafish protein, and both have N-terminal hydrophobic regions indicating microsomal localization. Northern blot analysis of P450RAI expression in several human cell lines showed that expression of P450RAI can be induced in response to retinoic acid, expressed constitutively, or not expressed at all, suggesting that its regulation is complex and may be tissue type dependent. White et al. (1997) showed that P450RAI mRNA expression is highly induced by retinoic acid in certain human tumor cell lines and that retinoic acid-inducible retinoic acid metabolism may correlate with P450RAI expression. The authors concluded that CYP26A1 plays a key role in regulating cellular retinoic acid levels in a feedback loop controlled by retinoic acid.
Lee et al. (2007) stated that the CYP26A1 gene contains 8 exons.
By fluorescence in situ hybridization, White et al. (1998) mapped the CYP26A1 gene to human chromosome 10q23-q24 and mouse chromosome 19C2-3.
Lee et al. (2007) sequenced the CYP26A1 gene in 92 racially and ethnically diverse individuals and identified 13 SNPs. Three SNPs produced changes in the coding region: a heterozygous 558C-A transversion, resulting in a phe186-to-leu (F186L) substitution, found in 1 of 24 Caucasians; a heterozygous 517C-A transversion, resulting in an arg173-to-ser (R173S) substitution, found in 3 of 15 African-Americans; and a heterozygous 1072T-C transition, resulting in a cys358-to-arg (C358R) substitution, found in 1 of 24 Asians. COS-1 cells transfected with wildtype CYP26A1 or the R173S variant metabolized all-trans retinoic acid at comparable rates. However, cells transfected with the F186L or C358R variants exhibited significantly lower metabolism of all-trans retinoic acid.
Cyp26a1 -/- mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess retinoic acid administration, indicating that human CYP26A1 may be essential in controlling retinoic acid levels during development. This hypothesis suggested that the Cyp26a1 -/- phenotype could be rescued under conditions in which embryonic retinoic acid levels are decreased. Niederreither et al. (2002) showed that indeed Cyp26a1-null mice are phenotypically rescued by heterozygous disruption of Aldh1a2 (603687), which encodes a retinaldehyde dehydrogenase responsible for the synthesis of retinoic acid during early embryonic development. Aldh1a2 haploinsufficiency prevented the appearance of spina bifida and rescued the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in Cyp26a1 -/- mice. Some of these double-mutant mice could reach adulthood. Thus, Niederreither et al. (2002) provided genetic evidence that ALDH1A2 and CYP26A1 activities concurrently establish local embryonic retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent spina bifida.
Kinkel et al. (2009) found that Cyp26a1 was expressed in the zebrafish anterior trunk endoderm at the appropriate developmental stage and location to regulate RA-dependent pancreas specification. Blocking Cyp26 function significantly enlarged the pancreatic field toward the anterior. Cyp26a1 played the primary role in this process, but in the absence of functional Cyp26a1, the Cyp26b1 (605207) and Cyp26c1 (608428) genes partially compensated for its loss.
Kinkel, M. D., Sefton, E. M., Kikuchi, Y., Mizoguchi, T., Ward, A. B., Prince, V. E. Cyp26 enzymes function in endoderm to regulate pancreatic field size. Proc. Nat. Acad. Sci. 106: 7864-7869, 2009. [PubMed: 19416885] [Full Text: https://doi.org/10.1073/pnas.0813108106]
Lee, S.-J., Perera, L., Coulter, S. J., Mohrenweiser, H. W., Jetten, A., Goldstein, J. A. The discovery of new coding alleles of human CYP26A1 that are potentially defective in the metabolism of all-trans retinoic acid and their assessment in a recombinant cDNA expression system. Pharmacogenet. Genomics 17: 169-180, 2007. [PubMed: 17460545] [Full Text: https://doi.org/10.1097/FPC.0b013e32801152d6]
Niederreither, K., Abu-Abed, S., Schuhbaur, B., Petkovich, M., Chambon, P., Dolle, P. Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nature Genet. 31: 84-88, 2002. [PubMed: 11953746] [Full Text: https://doi.org/10.1038/ng876]
White, J. A., Beckett-Jones, B., Guo, Y.-D., Dilworth, F. J., Bonasoro, J., Jones, G., Petkovich, M. cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450 (CYP26). J. Biol. Chem. 272: 18538-18541, 1997. [PubMed: 9228017] [Full Text: https://doi.org/10.1074/jbc.272.30.18538]
White, J. A., Beckett, B., Scherer, S. W., Herbrick, J.-A., Petkovich, M. P450RAI (CYP26A) maps to human chromosome 10q23-q24 and mouse chromosome 19C2-3. Genomics 48: 270-272, 1998. [PubMed: 9521883] [Full Text: https://doi.org/10.1006/geno.1997.5157]