Inactivating Mutations in the 25-Hydroxyvitamin D<sub>3</sub>1α-Hydroxylase Gene in Patients with Pseudovitamin D–Deficiency Rickets

Kitanaka, Susumu; Takeyama, Ken-ichi; Murayama, Akiko; Satō, Takashi; Okumura, Katsuhiko; Nogami, Masahiro; Hasegawa, Yukihiro; Niimi, Hiroo; Yanagisawa, Junn; Tanaka, Toshiaki; Kato, Shigeaki

doi:10.1056/nejm199803053381004

Cited by 344 publications

(183 citation statements)

References 34 publications

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“…This is reflected by mutations in the genes encoding 25-hydroxyvitamin D 3 -1α-hydroxylase (1α-OHase), a renal enzyme controlling its synthesis, and the 1,25(OH) 2 D 3 -receptor (VDR; Hughes et al 1988;Kitanaka et al 1998). As TRPV5 and TRPV6 form the ratelimiting entry step in active Ca 2+ (re)absorption, regulation of these channels by 1,25(OH) 2 D 3 has been investigated using different vitamin D-deficiency models.…”

Section: Vitamin Dmentioning

confidence: 99%

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The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Abel

Hoenderop

Bindels

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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The epithelial Ca 2+ channels TRPV5 and TRPV6 represent a new family of Ca 2+ channels that belongs to the superfamily of transient receptor potential channels. TRPV5 and TRPV6 constitute the apical Ca 2+ entry mechanism in active Ca 2+ transport in kidney and intestine. The central role of TRPV5 and TRPV6 in active Ca 2+ (re)absorption makes it a prime target for regulation to maintain Ca 2+ balance. This review covers the hormonal regulation, interaction with accessory proteins and (patho)physiological implications of these epithelial Ca 2+ channels.

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Section: Vitamin Dmentioning

confidence: 99%

“…The disease is caused by mutations in the 1α-OHase gene (Dardenne et al 2001;Kitanaka et al 1998). In clinical practice, patients are treated with vitamin D analogues and/ or an enriched Ca 2+ diet to prevent rickets, which correct the major perturbations in Ca 2+ homeostasis.…”

Section: Vitamin D-deficiency Ricketsmentioning

confidence: 99%

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Abel

Hoenderop

Bindels

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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“…This mitochondrial protein is expressed in the proximal renal tubules where activation of vitamin D 3 takes place (11)(12)(13). As predicted from the biosynthetic pathway, mutations in the gene encoding CYP27B1 cause selective 1␣,25-dihydroxyvitamin D 3 deficiency (also referred to as vitamin D-dependent rickets type I) in both humans (14) and mice (15), in which 25-hydroxyvitamin D 3 accumulates in plasma and levels of 1␣,25-dihydroxyvitamin D 3 are low (16).…”

mentioning

confidence: 99%

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

Cheng

Levine

Bell

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

643

387

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The synthesis of bioactive vitamin D requires hydroxylation at the 1␣ and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1␣-hydroxylation in the kidney but the identity of the hepatic 25-hydroxylase has remained unclear for >30 years. We previously identified the microsomal CYP2R1 protein as a potential candidate for the liver vitamin D 25-hydroxylase based on the enzyme's biochemical properties, conservation, and expression pattern. Here, we report a molecular analysis of a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity. These data identify CYP2R1 as a biologically relevant vitamin D 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency.T he metabolic pathway leading to the synthesis of active vitamin D involves three reactions that occur in different tissues (1). The pathway is initiated in the skin with the UV light-mediated cleavage of 5,7,-cholestadien-3␤-ol to produce the secosteroid (3␤,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol (vitamin D 3 ). The second step occurs in the liver and is catalyzed by a cytochrome P450 (CYP) enzyme that hydroxylates carbon 25, producing the intermediate 25-hydroxyvitamin D 3 , which is the major circulatory form of the vitamin. The third and final step takes place in the kidney and involves 1␣-hydroxylation by another CYP, producing 1␣,25-dihydroxyvitamin D 3 . This product is a potent ligand of the vitamin D receptor (VDR) and mediates most of the physiological actions of the vitamin (1).Although the chemical and enzymatic steps in the vitamin D 3 biosynthetic pathway have been known for 30 years (1), the enzyme catalyzing the 25-hydroxylation step in the liver has never been identified. At least six CYPs can catalyze this reaction in vitro, including CYP2C11, CYP2D25, CYP3A4, CYP2J1, CYP27A1, and CYP2R1 (2-4). Of these CYPs, the two most viable candidates for the vitamin D 25-hydroxylase are CYP27A1 and CYP2R1 (2). Both enzymes are expressed in the liver and are conserved among species known to have an active vitamin D signaling pathway. However, mutations in the human and mouse genes encoding the mitochondrial CYP27A1 protein impair bile acid synthesis, but have no consequences for vitamin D metabolism (5-9). It is thus not clear whether the two vitamin D 3 25-hydroxylases represent an example of biological redundancy in an important biosynthetic pathway or whether CYP2R1 alone or some unidentified enzyme fulfills this essential role.In contrast to the uncertainty surrounding vitamin D 3 25-hydroxylase, the renal enzyme responsible for 1␣-hydroxylation of the vitamin...

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“…Mutations in the 1␣-hydroxylase gene are known to cause vitamin D-dependency rickets type I (VDDR-I) (2,(7)(8)(9). Patients afflicted with this disease are unable to maintain normal serum calcium and suffer from secondary hyperparathyroidism, rickets, and osteomalacia (10).…”

mentioning

confidence: 99%

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

Vanhooke

Prahl

Kimmel-Jehan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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. The second hydroxylation is catalyzed by the 25-hydroxyvitamin D 3 -1␣-hydroxylase (1␣-hydroxylase), a mitochondrial cytochrome P450 enzyme that is the product of the CYP27B1 gene (2-6). Activity of 1␣-hydroxylase is tightly regulated through complex mechanisms that depend on the circulating levels of calcium, phosphorus, parathyroid hormone, and 1,25(OH) 2 D 3 .Mutations in the 1␣-hydroxylase gene are known to cause vitamin D-dependency rickets type I (VDDR-I) (2, 7-9). Patients afflicted with this disease are unable to maintain normal serum calcium and suffer from secondary hyperparathyroidism, rickets, and osteomalacia (10). VDDR-I is cured by administration of physiological doses of 1,25(OH) 2 D 3 (11). Physiological doses of 25-OH-D 3 are noncurative, but high dose administration can be effective (11), presumably due to the ability of 25-OH-D 3 to bind and activate the vitamin D receptor when present in vast excess.The experiments reported by Fraser and Kodicek in 1970 (12) were the first to demonstrate the kidney as the major, if not the only, tissue in which 1,25(OH) 2 D 3 is produced under normal physiological conditions. Over the next several years, extrarenal production of 1,25(OH) 2 D 3 was convincingly demonstrated in pregnant nephrectomized rats and in an anephric patient suffering from sarcoidosis (13-15). In these cases, synthesis was localized to the placenta and the sarcoid macrophages (14,16,17). Production of 1,25(OH) 2 D 3 at other sites has remained a subject of much investigation. A number of research groups have reported 1␣-hydroxylase activity in cultured cells, including those of the skin, bone, cartilage, intestine, prostate, and vascular epithelium (18 -25). Bikle et al. (26) have also reported 1,25(OH) 2 D 3 production in perfused flaps of porcine skin. Local production of 1,25(OH) 2 D 3 has been proposed to regulate cellular function and͞or differentiation in an autocrine or paracrine fashion (18,19,24,27,28), and it has been suggested that keratinocytes could supply 1,25(OH) 2 D 3 to the systemic circulation when renal production of the hormone is impaired (26,29). Production of extrarenal 1,25(OH) 2 D 3 in these experiments is not supported, however, by in vivo metabolic studies in nephrectomized nonpregnant rats. In these studies, two independent research groups were unable to detect 3 H-1,25(OH) 2 D 3 in the tissue or plasma after administering a dose of 3 H-25-OH-D 3 of high specific radioactivity (30,31). These conflicting results demonstrate a need for further investigation of the in vivo expression of the 1␣-hydroxylase. We have approached such an investigation by using gene targeting to replace the 1␣-hydroxylase coding sequence with a bacterial lacZ gene controlled by the 1␣-hydroxylase promoter. The lacZ gene codes for ␤-galactosidase, whose activity is readily detected in situ through histochemical staining with X-Gal (32). Herein we report the successful production of 1␣-hydroxylase null mice harboring the lacZ gene and present our analysis of in vivo 1␣-hydroxylase...

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Inactivating Mutations in the 25-Hydroxyvitamin D₃1α-Hydroxylase Gene in Patients with Pseudovitamin D–Deficiency Rickets

Abstract: Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene are a cause of pseudovitamin D-deficiency rickets.

Cited by 344 publications

References 34 publications

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin

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Inactivating Mutations in the 25-Hydroxyvitamin D31α-Hydroxylase Gene in Patients with Pseudovitamin D–Deficiency Rickets

Abstract: Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene are a cause of pseudovitamin D-deficiency rickets.

Cited by 344 publications

References 34 publications

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D 3 -1α-hydroxylase promoter activity in the skin

Contact Info

Product

Resources

About

Inactivating Mutations in the 25-Hydroxyvitamin D₃1α-Hydroxylase Gene in Patients with Pseudovitamin D–Deficiency Rickets

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D ₃ -1α-hydroxylase promoter activity in the skin