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Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait
A Molin1, R Baudoin1, M Kaufmann1
1Department of Genetics and Reference Center for Rare Disorders of Calcium and Phosphorus Metabolism (A.M., N.C., N.R., M.-L.K.), University Hospital, 14033 Caen, France; University Caen Basse-Normandie (A.M., M.-L.K.), Medical School, Caen, France; Department of Endocrinology (R.B.), University Hospital, 33000 Bordeaux, France; Department of Biomedical and Molecular Sciences (M.K., M.W., Q.B., G.J.), Queen's University, Kingston, Canada; Department of Physiology (J.C.S.), Necker University Hospital, 75015 Paris, France; Department of Pediatrics (A.R.), University Hospital, 35200 Rennes, France; Department of Endocrinology (M.C.V.), University Hospital, 59000 Lille, France; Department of Pediatrics (P.E.), University Hospital, Caen, France; Department of Pediatrics (J.B.), University Hospital, 69000 Lyon, France; Department of Pediatrics (G.D.), Robert Debre Hospital, Assistance Publique-Hôpitaux de Paris, 75019 Paris, France; Nephrology & Pediatrics (G.K.-R.), University Hospital, 44093 Nantes, France; Endocrinology Research Centre (A.T.), Moscow 117036, Russia; and INSERM U1075 COMETE (M.-L.K.), University of Caen Basse-Normandy, 14032 Caen, France.
Context:
Loss-of-function mutations of CYP24A1 (which encodes the 25-OH-D3-24-hydroxylase) have recently been reported to cause hypercalcemia.
Objectives:
The aims of this study were: 1) to evaluate the frequency of CYP24A1 mutations in patients with medical history of hypercalcemia; 2) to show the clinical utility of a simultaneous assay of serum 25-hydroxyvitamin D3 (25-OH-D3) and 24,25-dihydroxyvitamin D3 (24,25-[OH]2D3) by liquid chromatography tandem mass spectrometry (LC-MS/MS); and 3) to investigate biochemical parameters in heterozygous gene carriers with CYP24A1 mutations.
Patients And Methods:
We screened for CYP24A1 mutations in 72 patients with serum calcium levels > 2.6 mmol/L and PTH levels < 20 pg/mL and recruited 24 relatives after genetic counseling for subsequent investigations. Vitamin D metabolite concentrations were assessed in a subset of patients by LC-MS/MS and results expressed as a ratio (R) of 25-OH-D3:24,25-(OH)2D3.
Results:
Twenty-five patients with hypercalcemia (35%) harbored CYP24A1 variations. Twenty (28%) had biallelic variations, mostly found in subjects with nephrocalcinosis or renal stones (19/20). Five patients, all neonates, were heterozygous, without renal disease. We describe 15 new variations leading to loss-of-function according to pathogenicity prediction programs, and we functionally characterized 5 of them in vitro. A dramatic increase of R, usually >80, was found in patients harboring biallelic mutations providing evidence in vivo for the loss of CYP24A1 activity. In contrast, R value remains <25 in patients without CYP24A1 mutations. Subjects carrying one mutant allele, hypercalcemic individuals, as well as gene-carrier relatives, had a detectable 24,25-(OH)2D3 level and R < 25, indicating normal 24-hydroxylase activity.
Conclusion:
CYP24A1 biallelic mutations are frequently found in patients presenting with hypercalcemia, low PTH, and renal disease. We confirm the accuracy and effectiveness of a novel blood test estimating the ratio between relevant vitamin D metabolites as a useful screening tool for CYP24A1 mutations. Haploinsufficiency is not associated with CYP24A1 deficiency.
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