CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait
| Autor: | P. Eckart, Georges Deschênes, Glenville Jones, Justine Bacchetta, Martin Kaufmann, M. Wraich, Nicolas Richard, Arnaud Molin, Amélie Ryckewaert, Jean-Claude Souberbielle, Marie-Christine Vantyghem, R. Baudoin, Q. Bonafiglia, Nadia Coudray, A. Tiulpakov, G. Kesler-Roussey, Marie-Laure Kottler |
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| Přispěvatelé: | Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon |
| Rok vydání: | 2015 |
| Předmět: |
Male
24 25-Dihydroxyvitamin D 3 Endocrinology Diabetes and Metabolism Metabolite Clinical Biochemistry 030232 urology & nephrology Parathyroid hormone medicine.disease_cause Biochemistry chemistry.chemical_compound 0302 clinical medicine Endocrinology Tandem Mass Spectrometry Vitamin D Child Vitamin D3 24-Hydroxylase ComputingMilieux_MISCELLANEOUS Aged 80 and over Mutation Middle Aged 3. Good health Parathyroid Hormone Child Preschool Female Adult medicine.medical_specialty Adolescent chemistry.chemical_element 030209 endocrinology & metabolism Context (language use) Calcium 03 medical and health sciences Young Adult CYP24A1 Internal medicine medicine Vitamin D and neurology Humans Aged [SDV.GEN]Life Sciences [q-bio]/Genetics business.industry Biochemistry (medical) Infant Newborn Infant Heterozygote advantage chemistry [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Hypercalcemia business Chromatography Liquid |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism Journal of Clinical Endocrinology and Metabolism, Endocrine Society, 2015, 100 (10), pp.E1343-E1352. ⟨10.1210/jc.2014-4387⟩ |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Loss-of-function mutations of CYP24A1 (which encodes the 25-OH-D3-24-hydroxylase) have recently been reported to cause hypercalcemia.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.We screened for CYP24A1 mutations in 72 patients with serum calcium levels2.6 mmol/L and PTH levels20 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.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, usually80, was found in patients harboring biallelic mutations providing evidence in vivo for the loss of CYP24A1 activity. In contrast, R value remains25 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 R25, indicating normal 24-hydroxylase activity.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. |
| Databáze: | OpenAIRE |
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