Thank you for the classification of GPCRs you provided in your post. I found quite a few similarities and differences between the disorders we chose for this assignment.
Familial hypocalciuric hypercalcemia (FHH) is an inherited disorder caused by mutations that have been identified both in the extracellular and in the transmembrane and connecting loop portions of the receptor. Fibrous dysplasia/McCune-Albright syndrome (FD/MAS), on the other hand, is sporadic rather than inherited. Activating mutations of arginine 201 of the G ? gene have been found in a mosaic distribution in tissues of affected individuals.
The CaR is expressed in numerous organs and tissues – parathyroids, kidney, and C cells of the thyroid and brain, therefore mutation in the CaSR gene results in various pathologies. For instance, activation of the receptor in the parathyroid hinders PTH secretion. In the kidney, CaR activation by increased extracellular Ca2+ stimulates renal calcium excretion. Loss of function of a single CaR allele in FHH causes relative insensitivity to Ca2+ in parathyroid and kidney, with resultant increased serum Ca2+, inappropriately high PTH secretion, and inappropriately low urinary calcium excretion. FD/MAS may have different manifestation as well. It can affect one bone (monstotic) or multiple (polyostotic), and may occur in isolation or in combination with café-au-lait spots and hyperfunctioning endocrinopathies.
FHH is usually a benign disease not resulting in morbidity due to the serum Ca2+ elevation. In contrast, total loss of function of both CaR alleles causes neonatal severe primary hyperparathyroidism (NSPHT) – a life-threatening pathology caused by very high serum Ca2+ concentrations, skeletal demineralization, and multi-glandular parathyroid hyperplasia. In case of FH/MAs, the time of occurrence of somatic G ? mutations is important as it determines the nature and distribution of the manifestations. When mutations occur very early in embryogenesis they can cause pleiotropic, potentially lethal manifestations, whereas those occurring much later cause focal diseases, like somatotroph tumors or monostotic fibrous dysplasia.


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