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Human 25-hydroxyvitamin D-1alpha-hydroxylase: cloning, mutations, and gene expression
1Department of Pediatrics, University of California, San Francisco 94143-0748, USA. aportale@peds.ucsf.edu
Pediatric Nephrology (Berlin, Germany)
|July 27, 2000
Summary
The gene for the vitamin D 1alpha-hydroxylase enzyme (P450c1alpha) was cloned, revealing its structure and location. Mutations in this gene cause vitamin D-dependent rickets type 1.
Area of Science:
- Biochemistry
- Genetics
- Endocrinology
Background:
- Vitamin D bioactivation is crucial for calcium homeostasis.
- The enzyme 1alpha-hydroxylase (P450c1alpha) catalyzes the rate-limiting step in vitamin D activation.
- Deficiency in 1alpha-hydroxylation leads to vitamin D-dependent rickets type 1.
Purpose of the Study:
- To describe the cloning and characterization of the P450c1alpha gene.
- To investigate mutations in P450c1alpha causing 1alpha-hydroxylase deficiency.
- To explore the regulation of P450c1alpha gene expression.
Main Methods:
- Gene cloning and sequencing from human, mouse, and rat tissues.
- Mutation analysis in patients with vitamin D-dependent rickets type 1.
- Studies on gene expression regulation by hormones and dietary factors in animal models.
Main Results:
- The human P450c1alpha gene was cloned, found to be 5 kb on chromosome 12 with nine exons.
- Twenty distinct mutations were identified in 31 patients with 1alpha-hydroxylase deficiency.
- Gene expression is regulated at the mRNA level by parathyroid hormone (PTH), calcium, phosphorus, and 1,25(OH)2D.
Conclusions:
- The cloning of the P450c1alpha gene provides insights into vitamin D metabolism.
- Mutations in P450c1alpha are the cause of vitamin D-dependent rickets type 1.
- Regulation of P450c1alpha gene expression involves transcriptional control by various factors.