title: Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis.
abstract: OBJECTIVE
  Hypercalciuria is the most common cause of kidney stone disease and genetic factors have an important role in nearly half of these cases. Recently loss-of-function mutations of CYP24A1, the gene encoding vitamin D 24-hydroxylase, were identified in idiopathic infantile hypercalcemia. We describe the clinical and molecular basis of severe long-standing kidney stone disease in adults caused by CYP24A1 mutations.
  
  
  METHODS
  Three subjects from 2 Israeli families with nephrolithiasis and nephrocalcinosis were clinically characterized. Genomic DNA was isolated from peripheral blood and sequencing of CYP24A1 was performed.
  
  
  RESULTS
  All subjects presented with severe kidney stone disease, the cause of which was not discovered for decades despite extensive evaluation. They all had hypercalciuria, nephrocalcinosis and intermittent hypercalcemia, and chronic kidney insufficiency developed in the oldest subject. All patients had a typical pattern of test results, including normal-high serum calcium, low parathyroid hormone levels, high vitamin D 25-(OH)D3 and 1,25-(OH)2D3, and low 24,25-(OH)2D3. Overall 3 CYP24A1 loss-of-function mutations were identified, including a homozygous deletion (delE143) in consanguinous family 1, and compound heterozygous mutations L409S and the novel W268-stop in family 2.
  
  
  CONCLUSIONS
  Loss-of-function mutations of CYP24A1 gene, encoding for 1,25-dihydroxyvitamin D3 24-hydroxylase, cause severe hypercalciuric nephrolithiasis and nephrocalcinosis. The mutations may present in adults and may lead to chronic renal insufficiency. Our results support a recessive mode of inheritance. CYP24A1 mutations should be considered in the differential diagnosis of hypercalciuric nephrolithiasis, especially as many adults are now prescribed supplemental oral vitamin D.
authors.affiliation: Department of Nephrology and Hypertension, the Chaim Sheba Medical Center, Tel-Hashomer, Israel. dganit.dinour@sheba.health.gov.il
authors.forename: Dganit
authors.initials: D
authors.lastname: Dinour
authors.forename: Pazit
authors.initials: P
authors.lastname: Beckerman
authors.forename: Liat
authors.initials: L
authors.lastname: Ganon
authors.forename: Karen
authors.initials: K
authors.lastname: Tordjman
authors.forename: Zemach
authors.initials: Z
authors.lastname: Eisenstein
authors.forename: Eli J
authors.initials: EJ
authors.lastname: Holtzman
mesh_terms: D000328:Adult; D003241:Consanguinity; D006801:Humans; D053565:Hypercalciuria / Q000235:genetics*; D007557:Israel; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009397:Nephrocalcinosis / Q000235:genetics*; D053040:Nephrolithiasis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
keywords: CT; ESWL®; PTH; computerized tomography; extracorporeal shock wave lithotripsy; hypercalcemia, infantile; hypercalciuria; iPTH; intact parathyroid hormone; nephrocalcinosis; nephrolithiasis; parathyroid hormone; vitamin D 24-hydroxylase