Functional properties of the PTH/PTHrP receptor.
The PTH/PTHrP receptor belongs to a novel family of G-protein-coupled receptors which also includes an insect receptor for a diuretic hormone and the protein encoded by a genomic DNA clone from Caenorhabditis elegans. Despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics when tested with either [Arg2, Tyr34]hPTH(1-34)amide or [Nle8.18, Tyr34]bPTH(7-34)-amide. These PTH analogs, and chimeras between rat/opossum and between rat/human PTH/PTHrP receptors, led to the identification of receptor residues that appear to be involved in ligand/receptor interaction and receptor activation, respectively. The search for mutations in the PTH/PTHrP receptor gene in genomic DNA of patients with pseudohypoparathyroidism type Ib (PHP-Ib) revealed several silent polymorphisms and a missense mutation in the receptor's tail region which did not affect receptor function. Mutations in the PTH/PTHrP receptor are therefore rarely, if at all, responsible for PHP-Ib. A mutation in the PTH/PTHrP receptor is, however, the most likely cause of Jansen-type metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism which is associated with severe hypercalcemia despite normal or low levels of circulating PTH and PTHrP. A missense mutation was identified which causes constitutive, ligand-independent receptor activation, and thus explains the laboratory and the growth-plate abnormalities in affected individuals.
Jüppner
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Department of Medicine, Massachusetts General Hospital, Boston, USA.
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D002678:Chimera; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004392:Dwarfism / Q000235:genetics; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009893:Opossums; D010281:Parathyroid Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011556:Pseudopseudohypoparathyroidism / Q000235:genetics; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014162:Transfection
D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D004247:DNA