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Etude des causes génétiques de dérégulation du métabolisme de la vitamine D

Abstract : The vitamin D (D3 or cholecalciferol from animal kingdom and D2 or ergosterol from plan kingdom) is a pleiotropic hormone who has numerous biological effects including the regulation of calcium and phosphate metabolism. In humans, this compound is synthetized in skin in an inactive form. Thus, we call vitamin D metabolism the biological process which leads to the production of active metabolites (by enzymes 25- and 1α-hydroxylases encoded by CYP2R1 and CYP27B1 genes) and its degradation by vitamin D 24-hydroxylase (gene CYP24A1). The expression of 1α- and 24-hydroxylases is tightly and inversely regulated to maintain calcium and phosphate homeostasis, thanks to several feedback loops including 1,25-dihydroxyvitamin D and its receptor VDR, serum calcium and parathormone, serum phosphate and FGF23. Vitamin D deficiency and vitamin D activation deficiency are associated with rickets, while vitamin D excess are associated with hypercalcemia-hypercalciuria due to vitamin D intoxication (overdose) or hypersensitivity to vitamin D (activation excess or degradation deficiency).Our aim is to identify genetic causes of vitamin D metabolism deregulation and to specify pathophysiologic mechanisms describing phenotype. Thus, we jointly used the tools of genetics (next-generation and Sanger sequencing) and biochemistry (vitamin D metabolites assay) in a cohort of human patients ascertained thanks to the national center for rare diseases of calcium and phosphate metabolism.This work allowed us to specify the role of two genes in diseases of vitamin D metabolism, CYP2R1 and CYP24A1, showing loss of function mutations in patients with rickets and low 25-hydroxyvitamin D and hypersensitivity to vitamin D, respectively. Our study brought new phenotypic elements in these affections. In our cohort of patients, the identification of mutations leading to phosphate deregulation (in SLC34A1 and SLC34A3) highlights the putative role of regulators of vitamin D 1α- and 24-hydroxylases activities in pathophysiology.No significant variation have been identified in the proximal promoting regions of CYP27B1 and CYP24A1. We could not go further considering the lack of knowledge in regulating regions and factors in humans. Identifying distal regulators will allow to study their implication in rare diseases of vitamin D metabolism.
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Arnaud Molin. Etude des causes génétiques de dérégulation du métabolisme de la vitamine D. Médecine humaine et pathologie. Normandie Université, 2019. Français. ⟨NNT : 2019NORMC405⟩. ⟨tel-02349147⟩



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