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CYTOCHROME P450, SUBFAMILY XXVIB, POLYPEPTIDE 1; CYP26B1

CYTOCHROME P450, SUBFAMILY XXVIB, POLYPEPTIDE 1; CYP26B1

Alternative titles; symbolsCYTOCHROME P450, SUBFAMILY XXVIA, POLYPEPTIDE 2; CYP26A2P450, RETINOIC ACID-INACTIVATING, 2; P450RAI2HGNC Approved Gene Symbol: CYP26B...

Alternative titles; symbols

  • CYTOCHROME P450, SUBFAMILY XXVIA, POLYPEPTIDE 2; CYP26A2
  • P450, RETINOIC ACID-INACTIVATING, 2; P450RAI2

HGNC Approved Gene Symbol: CYP26B1

Cytogenetic location: 2p13.2 Genomic coordinates (GRCh38): 2:72,129,237-72,147,861 (from NCBI)

▼ Cloning and Expression
Retinoids, particularly all-trans-retinoic acid (RA), are important regulators of cell differentiation, cell proliferation, and apoptosis. All-trans-RA plays a role during development and in the maintenance of adult tissues. The level of all-trans-RA in cells and tissues is regulated by the balance between its biosynthesis and its catabolism to inactive metabolites. The cytochrome P450 enzyme P450RAI (CYP26A1; 602239), referred to by White et al. (2000) as P450RAI1, is partially responsible for the inactivation of all-trans-RA. White et al. (2000) identified an EST clone from a human retina cDNA library that showed significant sequence homology to P450RAI1. Using PCR primers, they amplified a partial cDNA, designated P450RAI2 (CYP26A2), encoding a 512-amino acid protein that is also involved in the specific inactivation of all-trans-RA. Northern blot analysis detected a 5-kb P450RAI2 transcript in most tissues tested, with highest expression in human adult brain, particularly in the cerebellum and pons but also in the cerebral cortex, medulla, occipital pole, frontal lobe, and temporal lobe. P450RAI1, on the other hand, did not show appreciable expression in any of the human brain tissues tested.

▼ Gene Function
White et al. (2000) found that transiently transfected P450RAI2 was capable of converting all-trans-RA to more polar metabolites. Competition experiments with other retinoids suggested that all-trans-RA is the preferred substrate.

▼ Molecular Genetics
In 3 sibs and an unrelated Turkish patient with radiohumeral fusions and other skeletal and craniofacial anomalies (614416), Laue et al. (2011) identified homozygous missense mutations in the CYP26B1 gene (R363L, 605207.0001, and S146P, 605207.0002, respectively).

▼ Animal Model
Yashiro et al. (2004) found that mice express Cyp26b1 in the distal region of the developing limb bud. Mice that lacked Cyp26b1 exhibited severe limb malformations. The lack of Cyp26b1 resulted in spreading of the RA signal toward the distal end of the developing limb and induced proximodistal patterning defects characterized by expansion of proximal identity and restriction of distal identity. Cyp26b1 deficiency also induced pronounced apoptosis in the developing limb and delayed chondrocyte maturation. Wildtype embryos exposed to excess RA phenocopied the limb defects of Cyp26b1-deficient mice. Yashiro et al. (2004) concluded that RA acts as a morphogen to determine proximodistal identity and that CYP26B1 prevents apoptosis and promotes chondrocyte maturation in the developing limb.

Bowles et al. (2006) found that retinoic acid, produced by mesonephroi of both sexes, caused germ cells in the ovary to enter meiosis and initiate oogenesis. Meiosis is retarded in the fetal testis by the action of the retinoid-degrading enzyme CYP26B1, ultimately leading to spermatogenesis. In testes of Cyp26b1-knockout mouse embryos, germ cells entered meiosis precociously, as if in a normal ovary. Thus, Bowles et al. (2006) concluded that precise regulation of retinoid levels during fetal gonad development provides the molecular control mechanism that specifies germ cell fate.

Laue et al. (2011) analyzed murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 and suggested that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicated that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning.

Using late Cyp26b1 -/- mouse embryos and mice with dermal-specific Cyp26b1 knockout, Okano et al. (2012) found that elevated dermal RA resulted in arrested hair follicle development, leading to decreased hair follicle density and abnormal hair orientation. Microarray analysis revealed that Cyp26b1 -/- skin showed downregulation of genes involved in hair follicle differentiation. Grafting Cyp26b1 -/- skin onto wildtype immunodeficient mice revealed that the effect of excess RA on hair growth was reversible.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 RADIOHUMERAL FUSIONS WITH OTHER SKELETAL AND CRANIOFACIAL ANOMALIES
CYP26B1, ARG363LEU
In 3 sibs, born to first-cousin parents, who exhibited combinations of severe craniofacial malformation, occipital encephalocele, radiohumeral fusions, oligodactyly, advanced osseous maturation, and calvarial mineralization defects (614416), Laue et al. (2011) identified homozygosity for a 1088G-T transversion in the CYP26B1 gene, predicting an arg363-to-leu (R363L) substitution. Both parents were heterozygous for the mutation, which was not found in 190 unrelated control individuals. The mutation occurs within an EXXR motif that is highly conserved across species and all human CYP450 proteins. Substitutions of residues within this motif are known to ablate the catalytic properties of these enzymes. Cellular cotransfection of CYP26B1-expression constructs encoding the R363L substitution alongside an RA-responsive luciferase reporter gene demonstrated a significantly attenuated ability to metabolize exogenously applied RA in HEK293 cells (86% reduction). The reduction of enzymatic activity noted for the mutant protein was comparable to that conferred by a truncating mutation underlying a zebrafish cyp26b1 null allele, indicating that the human mutation constitutes a null allele.

.0002 RADIOHUMERAL FUSIONS WITH OTHER SKELETAL AND CRANIOFACIAL ANOMALIES
CYP26B1, SER146PRO
In a Turkish patient, born to consanguineous parents, with coronal and lambdoid craniosynostosis, a large sagittal skull defect, limited elbow extension, and arachnodactyly (614416), Laue et al. (2011) identified a homozygous 436T-C transition in the CYP26B1 gene, predicting a ser146-to-pro (S146P) substitution. Th3 mutation is predicted to disrupt helix C, a broadly represented structural element in CYP450 enzymes. Cellular cotransfection of CYP26B1-expression constructs encoding the S146P substitution alongside an RA-responsive luciferase reporter gene demonstrated a significantly attenuated ability to metabolize exogenously applied RA in HEK293 cells (31% reduction). The retention of activity by the S146P substitution was consistent with it constituting a hypomorphic mutation.

Tags: 2p13.2

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