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

Abstract

SummaryBackground and objectives Elevated serum vitamin D with hypercalciuria can result in nephrocalcinosis and nephrolithiasis. This study evaluated the cause of excess 1,25-dihydroxycholecalciferol (1a,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 (1a,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 1a,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%. ConclusionsThe 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.

Searching for CYP24A1 mutations in cohorts of patients with calcium nephrolithiasis

“…The second patient was described as a 38-year-old man, with recurrent (calcium phosphate) renal stones since the age of 25 and hyperkalaemia, hypercalciuria, suppressed PTH and elevation of 1,25(OH) 2 vitamin D. He also had bi-allelic mutations, a c.1226T>C, p.L409S change inherited from his mother and the c.428_430del; p.E143del mutation inherited from his father. Metabolic studies in both patients confirmed reduced enzyme function with undetectable activity of CYP24A1 15 .…”

“…This evidence for CYP24A1 variants contributing to nephrolithiasis was recently strengthened by a report detailing two patients with bi-allelic mutations in CYP24A1 15 . First, a 9-year-old boy with hypercalciuria, increased 1,25(OH) 2 vitamin D and medullary nephrocalcinosis was found to have compound heterozygous mutations (c.428_430del; p.E143del, previously reported by Schlingman 13 together with c.443T>C; p.L148P).…”

“…Considering this evidence, implicating CYP24A1 variants in calcium stone formation/nephrocalcinosis with specific biochemical phenotypes 15 could CYP24A1 be contributing to adult onset nephrolithiasis in the 'idiopathic' hypercalciuria population?…”

“…This was a reasonable strategy given both the previously reported cases and the noted frequency of potentially pathogenic non-synonymous sequence variants reported in dbSNP 15 . Two cohorts of renal stoneforming patients from the Northeast of England with metabolic phenotypes potentially consistent with loss of CYP24A1 function were screened.…”

“…Indeed, very recently a genetic analysis of two patients (a 9-year-old boy and a 38-year-old man) with elevated 1,25 (OH) 2 vitamin D, suppressed parathyroid hormone (PTH) and nephrocalcinosis or nephrolithiasis, respectively, were found to have bi-allelic mutations in CYP24A1 15 . Furthermore, the predicted frequency of some potentially pathogenic sequence variants within this gene is high, suggesting these variants may be important genetic risk factors for stone formation 15 . We therefore examined two cohorts of calcium stone formers with phenotypes that might be suggestive of an underlying defect in vitamin D metabolism mutations in CYP24A1.…”