1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis.

Abstract

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 show that 1,25(OH)2D-24-hydroxylase deficiency due to bi-allelic mutations in CYP24A1 causes elevated serum vitamin D, hypercalciuria, nephrocalcinosis, and renal stones.

• Authors: 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
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 8 Issue 4 Pg. 649-57 (Apr 2013) ISSN: 1555-905X [Electronic] United States
• PMID: 23293122 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Phosphates
• Vitamin D
• Steroid Hydroxylases
• CYP24A1 protein, human
• Vitamin D3 24-Hydroxylase
• Calcium

Topics

• Adult
• Calcium (blood)
• Child
• Family Health
• Female
• Humans
• Hypercalciuria (etiology, genetics, metabolism)
• Male
• Nephrocalcinosis (etiology, genetics, metabolism)
• Nephrolithiasis (etiology, genetics, metabolism)
• Pedigree
• Phosphates (blood)
• Primary Cell Culture
• Steroid Hydroxylases (deficiency, genetics)
• Vitamin D (blood)
• Vitamin D3 24-Hydroxylase