1,25-(OH)2D-24 hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis

Galina Nesterova, May Christine Malicdan, Kaori Yasuda, Toshiyuki Sakaki, Thierry Vilboux, Carla Ciccone, Ronald Horst, Yan Huang, Gretchen Golas, Wendy Introne, Marjan Huizing, David Adams, Cornelius F. Boerkoel, Michael T. Collins, William A. Gahl

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


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)2D3) 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)2D3), normal 25-OHD3, decreased 24,25(OH)2D, and undetectable activity of 1,25(OH)2D-24- hydroxylase (CYP24A1), the enzyme that inactivates 1α,25(OH)2D3. 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 showthat 1,25(OH)2D-24-hydroxylase deficiency due to bi-allelicmutations in CYP24A1 causes elevated serum vitamin D, hypercalciuria, nephrocalcinosis, and renal stones.

Original languageEnglish (US)
Pages (from-to)649-657
Number of pages9
JournalClinical Journal of the American Society of Nephrology
Issue number4
StatePublished - Apr 5 2013
Externally publishedYes

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation


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