GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

摘要: The calcium-sensing receptor (CASR) is the main calcium sensor in maintenance of metabolism. Mutations CASR, G protein alpha 11 (GNA11) and adaptor-related complex 2 sigma 1 subunit (AP2S1) genes can shift set point for sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts these rare diseases range from general therapies conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution allosteric CASR modulators. Cinacalcet a calcimimetic that enhances function has gained approval treatment hyperparathyroidism. Calcilytics turn attenuate activity are currently under investigation various diseases. We conducted literature search reports about patients harboring inactivating activating GNA11 AP2S1 mutants vitro effects modulators on mutated CASR. therapeutic with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), severe (NSHPT) autosomal dominant hypocalcemia (ADH) reviewed. FHH usually benign, but symptomatic benefit cinacalcet. In NSHPT pamidronate effectively lowers serum calcium, most require parathyroidectomy. some cinacalcet obviate need surgery, particularly heterozygous NHPT. Symptomatic ADH respond vitamin D supplementation this may increase calciuria renal complications. PTH reduce relative hypercalciuria. None available ADH, however, prevent tissue calcifications complications, which become possible calcilytics correct underlying pathophysiologic defect.