Clin J Am Soc Nephrol. 2013 Jan 4.
Nesterova G, Malicdan MC, Yasuda K, Sakaki T, Vilboux T, Ciccone C, Horst R, Huang Y, Golas G, Introne W, Huizing M, Adams D, Boerkoel CF, Collins MT, Gahl WA.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;,
†Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan;,
‡Heartland Assays, Ames, Iowa;,
§Undiagnosed Diseases Program, Office of Rare Diseases Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;,
‖Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland,
¶Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
BACKGROUND AND OBJECTIVES: Elevated serum vitamin D with hypercalciuria can result in nephrocalcinosis and nephrolithiasis. This study evaluated the cause of excess 1,25-dihydroxycholecalciferol (1α,25(OH)(2)D(3)) in the development of those disorders in two individuals.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Two patients with elevated vitamin D levels and nephrocalcinosis or nephrolithiasis were investigated at the National Institutes of Health (NIH) Clinical Center and the NIH Undiagnosed Diseases Program, by measuring calcium, phosphate, and vitamin D metabolites, and by performing CYP24A1 mutation analysis.
RESULTS: Both patients exhibited hypercalciuria, hypercalcemia, low parathyroid hormone, elevated vitamin D (1α,25(OH)(2)D(3)), normal 25-OHD(3), decreased 24,25(OH)(2)D, and undetectable activity of 1,25(OH)(2)D-24-hydroxylase (CYP24A1), the enzyme that inactivates 1α,25(OH)(2)D(3). Both patients had bi-allelic mutations in CYP24A1 leading to loss of function of this enzyme. On the basis of dbSNP data, the frequency of predicted deleterious bi-allelic CYP24A1 variants in the general population is estimated to be as high as 4%-20%.
CONCLUSIONS: The results of this study show that 1,25(OH)(2)D-24-hydroxylase deficiency due to bi-allelic mutations in CYP24A1 causes elevated serum vitamin D, hypercalciuria, nephrocalcinosis, and renal stones.
CYP24A1 gene inactivates 1α,25(OH)(2)D(3)
4% – 20% of people have a mutated CYP24A1 gene
Resulting high levels of 1α,25(OH)(2)D(3) (not detectable by vitamin D blood test) results in increased Calcium which causes kidney problems
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- CYP24A1 gene mutation is a cause of rare infant vitamin D toxicity – Aug 2011Mutations in CYP24A1 gene (vitamin D) associated with kidney problems – Jan 2013
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