Genetic Defect in<i>CYP24A1</i>, the Vitamin D 24-Hydroxylase Gene, in a Patient with Severe Infantile Hypercalcemia

Dauber, Andrew; Nguyen, Thutrang T.; Sochett, Etienne; Cole, David E. C.; Horst, Ronald L.; Abrams, Steven A.; Carpenter, Thomas O.; Hirschhorn, Joel N.

doi:10.1210/jc.2011-1972

Cited by 114 publications

(68 citation statements)

References 29 publications

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“…In 2011, Schlingmann et al ( 166 ) demonstrated that loss-offunction mutations of CYP24A1 were an underlying cause of IIH in nine families of German, Turkish, and Russian origin. This work, which recently confi rmed by other USbased groups (167)(168)(169), reinforced the important conclusion drawn from the CYP24A1-null mouse studies that CYP24A1 is primarily a catabolic enzyme.…”

Section: Downloaded Fromsupporting

confidence: 80%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

395

292

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signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

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Section: Downloaded Fromsupporting

confidence: 80%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

395

292

View full text Add to dashboard Cite

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“…CYP24A1 deficiency is a recently described cause of severe infantile neonatal hypercalcaemia [149,150].…”

Section: (B) Vitamin D 1a-hydroxylasementioning

confidence: 99%

Human cytochromes P450 in health and disease

Nebert

Wikvall

Miller

2013

Phil. Trans. R. Soc. B

438

305

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There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development.

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“…Depending on calcium and phosphorus demands, D (10, 11 ). Inactivating mutations of CYP24A1 (cytochrome P450, family 24, subfamily A, polypeptide 1) cause hypercalcemia, hypercalciuria, and increased 1,25(OH) 2 D concentrations (12)(13)(14)(15)(16)(17)(18)(19)(20). In studies describing LC-MS/MS assays for 24,25(OH) 2 D quantification, the relationship between 25(OH)D and 24,25(OH) 2 D has been used as a nutritional marker for assessment of optimum vitamin D supplementation (21 ).…”

Section: Hydroxyvitamin D [25(oh)d]mentioning

confidence: 99%