Hyperparathyroidism Clinical Trial
Official title:
Autotaxin in Patients With GNAS/PTH Abnormalities
PTH secretion defects (grouped under the name hypoparathyroidism) are due to abnormalities in the PTH gene, abnormalities in the development of the parathyroid glands which synthesize PTH or abnormalities of the calcium sening receptor whose role is to adapt PTH level to ambient calcium level. In contrast, primary hyperparathyroidism in children is also exceptional; expressed by hypercalcemia, with a renal and bon risk. Pseudo-hypoparathyroidism, now known under the term inactivating PTH / PTHrP Signaling Disorder or iPPSD, are rare pathologies characterized by resistance to the action of PTH sometimes associated with other symptoms, in particular chondrodysplasia. They are linked to a defect in the action of a factor in the signaling pathway of G protein-coupled receptors that activate the production of cyclic AMP (cAMP). IPPSDs are most often due to a molecular defect in the GNAS gene, subject to parental imprint. Fibrous dysplasia / McCune-Albright syndrome is a rare disease caused by somatic "gain-of-function" mutations in the GNAS gene located on chromosome 20q13 leading to activation of the protein Gαs and inappropriate production of intracellular cyclic adenosine monophosphate (cAMP). The clinical phenotype is determined by the location and extent of the tissues affected by this mutation. Autotaxin (ATX) is a protein secreted by different tissues including the liver, fatty tissue, and bone. Today, ATX is described as the major source of LPA in the bloodstream. LPA interacts with one of its receptors on the surface of the cell membrane. Depending on the receptor engaged, one or more Gα subunits (G12 / 13, GQ, Gi / o or Gs) will activate multiple cell signaling pathways. In bone, ATX is expressed by osteoclasts and osteoblasts. Recent laboratory data have shown that PTH stimulates ATX expression in osteoblasts in a dose-dependent manner. The objective of this study is to provide clinical proof of concept that the PTH / Gαs / ATX pathway is truly significant in physiology and pathology, by studying the full spectrum of PTH and GNAS pathologies. If this proof of concept is obtained, therapeutic applications will probably be possible in the long term.
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