Alternative titles; symbols
HGNC Approved Gene Symbol: CYP24A1
Cytogenetic location: 20q13.2 Genomic coordinates (GRCh38): 20:54,143,538-54,173,986 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.2 | Hypercalcemia, infantile, 1 | 143880 | Autosomal recessive | 3 |
1,25-Dihydroxyvitamin D3, the physiologically active form of vitamin D3, exerts its functions through a receptor (VDR; 601769)-mediated mechanism. In addition to its fundamental role in calcium metabolism, 1,25-(OH)2D3 acts on a variety of tissues. One of its most important functions is its differentiating activity. The best-characterized incidence of this activity is induction of differentiation of promyelocytes into monocytes/macrophages. 1,25-(OH)2D3 is biologically inactivated through a series of reactions beginning with 24-hydroxylation. 1,25-(OH)2D3 induces the 24-hydroxylase, whereas hypocalcemia, through increased parathyroid hormone, suppresses this enzyme. Chen et al. (1993) isolated the cDNA encoding the human 24-hydroxylase, sequenced it, and demonstrated that it is active when expressed in genetic expression systems.
Vitamin D 24-hydroxylase is a mitochondrial enzyme responsible for inactivating vitamin D metabolites through the C-24 oxidation pathway. Ohyama et al. (1991) isolated a cDNA encoding 25-hydroxyvitamin D(3)24-hydroxylase from a rat kidney cDNA library by use of specific antibodies to the enzyme. The amino acid sequence showed less than 30% similarity to those of previously reported cytochrome P450s.
Labuda et al. (1993) cloned part of the CYP24 gene: 776 bp of the coding and 720 bp of the 3-prime untranslated region interrupted by an intron. In the coding region, they found 79.8% similarity in DNA and 87.5% similarity in deduced amino acid sequence between human and rat, with no similarity in the 3-prime untranslated region.
Independently, Hahn et al. (1993) isolated a human kidney cDNA clone for vitamin D 24-hydroxylase.
Chen and DeLuca (1995) determined that the promoter region of CYP24 contains a TATA box, a CAAT box, GC boxes, 2 vitamin D-responsive elements (VDREs), and AP1 (165160)- and AP2 (107580)-binding sites. Functional characterization of the VDREs indicated that both are required for optimal induction of CYP24 expression by 1,25-dihydroxyvitamin D3.
By Southern blot hybridization of DNA from human-hamster somatic cell hybrids and by in situ immunofluorescence hybridization, Labuda et al. (1993) mapped the CYP24 gene to 20q13.1. Hahn et al. (1993) mapped the CYP24 gene to 20q13.2-q13.3 by fluorescence in situ hybridization.
By study of an interspecific backcross, Malas et al. (1994) demonstrated that the mouse homolog is located on chromosome 2 in a region of conserved synteny with human chromosome 20.
Using DNA microarray and quantitative PCR analyses, Liu et al. (2006) found that activation of TLR2 (603028) and TLR1 (601194) by a mycobacterial ligand upregulated expression of VDR and CYP27B1 (609506), the vitamin D 1-hydroxylase that catalyzes the conversion of vitamin D to its active form, in monocytes and macrophages, but not dendritic cells. Intracellular flow cytometric and quantitative PCR analyses showed that treatment of monocytes with vitamin D upregulated expression of CYP24 and cathelicidin (CAMP; 600474), an antimicrobial peptide, but not DEFB4 (602215). Confocal microscopy demonstrated colocalization of CAMP with bacteria-containing vacuoles of vitamin D-treated monocytes, and vitamin D treatment of M. tuberculosis-infected macrophages reduced the number of viable bacilli. Ligand stimulation of TLR2 and TLR1 upregulated CYP24 and CAMP in the presence of human serum, but not bovine serum, and CAMP upregulation was more efficient in Caucasian than in African American serum, in which vitamin D levels were significantly lower. Vitamin D supplementation of African American serum reversed the CAMP induction defect. Liu et al. (2006) proposed that vitamin D supplementation in African and Asian populations, which may have a reduced ability to synthesize vitamin D from ultraviolet light in sunlight, might be an effective and inexpensive intervention to enhance innate immunity against microbial infection and neoplastic disease.
Using array comparative genomic hybridization (CGH), Albertson et al. (2000) resolved 2 regions of amplification within an approximately 2-Mb region of recurrent aberration at 20q13.2 in breast cancer (114480). The putative oncogene ZNF217 (602967) mapped to one peak, and CYP24, whose overexpression is likely to lead to abrogation of growth control mediated by vitamin D, mapped to the other. Fine mapping demonstrated that ZNF217 lies proximal to CYP24. As transcription of CYP24 is closely coupled to the level and activity of VDR, Albertson et al. (2000) measured both CYP24 and VDR transcript levels using quantitative PCR in breast tumors. Expression of CYP24, normalized with respect to VDR, correlated with copy number of CYP24 in the tumors, further supporting an oncogenic role for CYP24.
In 7 patients from 8 unrelated families with infantile hypercalcemia-1 (HCINF1; 143880), Schlingmann et al. (2011) identified homozygosity or compound heterozygosity for mutations in the CYP24A1 gene (see, e.g., 126065.0001-126065.0007). In 1 patient, a heterozygous complex deletion in CYP24A1 was identified, but no other mutation was detected by sequence analysis. Overexpression of the mutant CYP24A1 enzymes in a eukaryotic cell line revealed complete or near-complete loss of function for all identified mutations.
In molecular-modeling simulations, Ji and Shen (2011) found that among the 4 missense mutations reported by Schlingmann et al. (2011), only L409S (126065.0006) weakens the binding of 1,25-dihydroxyvitamin D3 to 24-hydroxylase. Noting that the catabolism of 1,25-dihydroxyvitamin D3 by 24-hydroxylase is heme-dependent, Ji and Shen (2011) analyzed the influence of these mutations on heme binding and found that the other 3 mutations, R159Q (126065.0004), R396W (126065.0005), and E322K (126065.0007), all change interactions between the heme molecule and 24-hydroxylase.
In a 47-year-old man who had an episode of nephrolithiasis at 19 years of age and was subsequently asymptomatic until hypercalcemia was discovered on routine testing at 39 years of age, Streeten et al. (2011) identified homozygosity for a 3-bp deletion in the CYP24A1 gene (E143del; 126065.0002). Streeten et al. (2011) noted that this mutation had been identified by Schlingmann et al. (2011) in patients with infantile hypercalcemia. Noting that vitamin D prophylaxis was a factor in the development of symptomatic hypercalcemia in the children reported by Schlingmann et al. (2011), Schlingmann et al. (2011) suggested that information on lifestyle, nutrition, and vitamin supplementation in the patient described by Streeten et al. (2011) might identify a potential trigger for clinical symptoms in adulthood.
Ogunkolade et al. (2006) hypothesized that chewing betel nut, an addictive habit common throughout South Asian communities, contributes to hypovitaminosis D by modulating the enzymes regulating circulating activated vitamin D (1,25-dihydroxyvitamin D) concentration. Peripheral blood mononuclear cell 24-hydroxylase (CYP24A1) mRNA correlated positively and serum 1,25-dihydroxyvitamin D negatively with betel quids per day. Betel chewing is a more powerful independent determinant of increased 24-hydroxylase expression and of decreased serum calcitriol than serum 25-dihydroxyvitamin D, supporting the hypothesis that this habit could aggravate the effects of vitamin D deficiency.
Kasuga et al. (2002) found that transgenic rats constitutively expressing CYP24 showed significantly low levels of plasma 24,25-dihydroxyvitamin D3. They also developed albuminuria and hyperlipidemia shortly after weaning. Plasma lipid profiles revealed that all lipoprotein fractions were elevated. Transgenic rats showed atherosclerotic lesions in the aorta, which progressed with high-fat and high-cholesterol feeding.
In a female infant, born of consanguineous Turkish parents, who developed infantile hypercalcemia (HCINF1; 143880) while receiving a 500 IU daily dose of vitamin D, Schlingmann et al. (2011) identified homozygosity for a 2-bp deletion (1425delTC) in the CYP24A1 gene, resulting in a frameshift and predicted to cause premature termination of the protein (Ala475fsTer490). The mutation was not found in at least 204 control alleles, and transfection studies demonstrated complete loss of CYP24A1 catabolic activity with the mutant compared to wildtype.
In monozygotic twin brothers from a German family, who developed infantile hypercalcemia (HCINF1; 143880) while receiving a 500 IU daily dose of vitamin D, Schlingmann et al. (2011) identified compound heterozygosity for a 3-bp deletion (427delGAA) in the CYP24A1 gene, resulting in the in-frame deletion of a glutamic acid residue at codon 143 (E143del), and a 451G-T transversion, resulting in a gln151-to-ter (E151X; 126065.0003) substitution. In a Turkish infant who also developed hypercalcemia on 500 IU per day of vitamin D, Schlingmann et al. (2011) identified compound heterozygosity for the 3-bp deletion and a 476G-A transition in the CYP24A1 gene, resulting in an arg159-to-gln (R159Q; 126065.0004) substitution. The mutations were not found in at least 204 control alleles, and transfection studies demonstrated ablation of CYP24A1 catabolic activity with either the 3-bp deletion or the R159Q mutation compared to wildtype.
In a 47-year-old man who had an episode of nephrolithiasis at 19 years of age and was subsequently asymptomatic until hypercalcemia was discovered on routine testing at 39 years of age (see 143880), Streeten et al. (2011) identified homozygosity for the E143del mutation in CYP24A1. The patient had a suppressed parathyroid hormone level, elevated levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and low levels of 24,25-dihydroxyvitamin D. His adult son with normocalciuria was heterozygous for the E143del mutation.
For discussion of the glu151-to-ter (E151X) mutation in the CYP24A1 gene that was found in compound heterozygous state in twins with infantile hypercalcemia (HCINF1; 143880) by Schlingmann et al. (2011), see 126065.0002.
For discussion of the arg159-to-gln (R159Q) mutation in the CYP24A1 gene that was found in compound heterozygous state in a patient with infantile hypercalcemia (HCINF1; 143880) by Schlingmann et al. (2011), see 126065.0002.
In molecular-modeling simulations, Ji and Shen (2011) found that the R159Q mutation changes interactions between the heme molecule and 24-hydroxylase, due to destruction of hydrogen bonds between the heme propionate group and arginine.
In a German patient who developed infantile hypercalcemia (HCINF1; 143880) following a 600,000 IU oral dose of vitamin D, Schlingmann et al. (2011) identified homozygosity for a 1186C-T transition in the CYP24A1 gene, resulting in an arg396-to-trp (R396W) substitution. In 2 Russian brothers who developed infantile hypercalcemia while taking 500 IU of vitamin D per day, the R396W mutation was found in compound heterozygosity with a 1226T-C transition in the CYP24A1 gene, resulting in a leu409-to-ser (L409S; 126065.0006) substitution; and in 2 unrelated patients from Germany who developed hypercalcemia of infancy after 2 and 3 oral boluses of 600,000 IU of vitamin D, respectively, previously reported by Misselwitz and Hesse (1986), Schlingmann et al. (2011) identified compound heterozygosity for the R396W mutation and a 964G-A transition in CYP24A1, resulting in a glu322-to-lys (E322K; 126065.0007) substitution. The E322K mutation was not found in at least 204 control alleles; the R396W and L409S mutations, which had previously been annotated as putative polymorphisms in the dbSNP database, were tested in a sample of 1,024 control alleles, and L409S was not detected, but R396W was identified in 4 of the control alleles. Transfection studies demonstrated that R396W and E322K mutations resulted in complete loss of CYP24A1 catabolic activity, whereas the L409S mutation retained small but measurable levels of activity.
In molecular-modeling simulations, Ji and Shen (2011) found that the R396W mutation changes interactions between the heme molecule and 24-hydroxylase, due to destruction of hydrogen bonds between the heme propionate group and arginine.
For discussion of the leu409-to-ser (L409S) mutation in the CYP24A1 gene that was found in compound heterozygous state in 2 sibs with infantile hypercalcemia (HCINF1; 143880) by Schlingmann et al. (2011), see 126065.0005.
In molecular-modeling simulations, Ji and Shen (2011) found that the L409S mutation weakens the binding of 1,25-dihydroxyvitamin D3 to 24-hydroxylase.
For discussion of the glu322-to-lys (E322K) mutation in the CYP24A1 gene that was found in compound heterozygous state in 2 patients with infantile hypercalcemia (HCINF1; 143880) by Schlingmann et al. (2011), see 126065.0005.
In molecular-modeling simulations, Ji and Shen (2011) found that the E322K mutation changes interactions between the heme molecule and 24-hydroxylase. Schlingmann et al. (2011) stated that the E322K mutation abolishes important hydrogen bonding between the I-helix and the B-prime/C loop backbone, affecting their relative orientation and that of the B-prime helix and thereby preventing correct protein folding and stability.
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Chen, K.-S., DeLuca, H. F. Cloning of the human 1-alpha,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim. Biophys. Acta 1263: 1-9, 1995. [PubMed: 7632726] [Full Text: https://doi.org/10.1016/0167-4781(95)00060-t]
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Hahn, C. N., Baker, E., Laslo, P., May, B. K., Omdahl, J. L., Sutherland, G. R. Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2-q13.3. Cytogenet. Cell Genet. 62: 192-193, 1993. [PubMed: 8440135] [Full Text: https://doi.org/10.1159/000133473]
Ji, H.-F., Shen, L. CYP24A1 mutations in idiopathic infantile hypercalcemia. (Letter) New Eng. J. Med. 365: 1741 only, 2011. [PubMed: 22047571] [Full Text: https://doi.org/10.1056/NEJMc1110226]
Kasuga, H., Hosogane, N., Matsuoka, K., Mori, I., Sakura, Y., Shimakawa, K., Shinki, T., Suda, T., Taketomi, S. Characterization of transgenic rats constitutively expressing vitamin D-24-hydroxylase gene. Biochem. Biophys. Res. Commun. 297: 1332-1338, 2002. [PubMed: 12372434] [Full Text: https://doi.org/10.1016/s0006-291x(02)02254-4]
Labuda, M., Lemieux, N., Tihy, F., Prinster, C., Glorieux, F. H. Human 25-hydroxyvitamin D 24-hydroxylase cytochrome P450 subunit maps to a different chromosomal location than that of pseudovitamin D-deficient rickets. J. Bone Miner. Res. 8: 1397-1406, 1993. [PubMed: 8266831] [Full Text: https://doi.org/10.1002/jbmr.5650081114]
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Malas, S., Peters, J., Abbott, C. The genes for endothelin 3, vitamin D 24-hydroxylase, and melanocortin 3 receptor map to distal mouse chromosome 2, in the region of conserved synteny with human chromosome 20. Mammalian Genome 5: 577-579, 1994. [PubMed: 8000144] [Full Text: https://doi.org/10.1007/BF00354934]
Misselwitz, J., Hesse, V. Hypercalcemia following prophylactic vitamin D administration. Kinderarztl. Prax. 54: 431-438, 1986. [PubMed: 3490596]
Ogunkolade, W. B., Boucher, B. J., Busitn, S. A., Burrin, J. M., Noonan, K., Mannan, N., Hitman, G. A. Vitamin D metabolism in peripheral blood mononuclear cells is influenced by chewing 'betel nut' (Areca catechu) and vitamin D status. J. Clin. Endocr. Metab. 91: 2612-2617, 2006. [PubMed: 16670168] [Full Text: https://doi.org/10.1210/jc.2005-2750]
Ohyama, Y., Noshiro, M., Okuda, K. Cloning and expression of cDNA encoding 25-hydroxyvitamin D(3) 24-hydroxylase. FEBS Lett. 278: 195-198, 1991. [PubMed: 1991512] [Full Text: https://doi.org/10.1016/0014-5793(91)80115-j]
Schlingmann, K. P., Jones, G., Konrad, M. Reply to Streeten et al. and Ji and Shen. (Letter) New Eng. J. Med. 365: 1742-1743, 2011.
Schlingmann, K. P., Kaufmann, M., Weber, S., Irwin, A., Goos, C., John, U., Misselwitz, J., Klaus, G., Kuwertz-Broking, E., Fehrenbach, H., Wingen, A. M., Guran, T., Hoenderop, J. G., Bindels, R. J., Prosser, D. E., Jones, G., Konrad, M. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. New Eng. J. Med. 365: 410-421, 2011. [PubMed: 21675912] [Full Text: https://doi.org/10.1056/NEJMoa1103864]
Streeten, E. A., Zarbalian, K., Damcott, C. M. CYP24A1 mutations in idiopathic infantile hypercalcemia. (Letter) New Eng. J. Med. 365: 1741-1742, 2011. [PubMed: 22047572] [Full Text: https://doi.org/10.1056/NEJMc1110226]