title: 1,25-(OH)2D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. nesterovag@mail.nih.gov
authors.forename: Galina
authors.initials: G
authors.lastname: Nesterova
authors.forename: May Christine
authors.initials: MC
authors.lastname: Malicdan
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.forename: Carla
authors.initials: C
authors.lastname: Ciccone
authors.forename: Ronald
authors.initials: R
authors.lastname: Horst
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.forename: Wendy
authors.initials: W
authors.lastname: Introne
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000328:Adult; D002118:Calcium / Q000097:blood; D002648:Child; D005192:Family Health; D005260:Female; D006801:Humans; D053565:Hypercalciuria / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D009397:Nephrocalcinosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D053040:Nephrolithiasis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010710:Phosphates / Q000097:blood; D061251:Primary Cell Culture; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics*; D014807:Vitamin D / Q000097:blood; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D010710:Phosphates; D014807:Vitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002118:Calcium