INACTIVATING MUTATION IN THE HUMAN PARATHYROID-HORMONE RECEPTOR-TYPE-1 GENE IN BLOMSTRAND-CHONDRODYSPLASIA

ii single homozygous nucleotide exchange in exon E3 of the gene encodi ng the parathyroid hormone receptor type 1 (PTHR1) was identified in a n infant with Blomstrand chondrodysplasia born to consanguineous paren ts. This alteration changes a strictly conserved proline residue at po sition 132 in the receptor's amino terminal extracellular domain to le ucine. COS-1 cells expressing the mutant receptor did not accumulate c yclic adenosine 3',5'-monophosphate in response to PTH or PTH-related peptide (PTHrP) and did not bind the radiolabeled ligand. Expression o f the mutant protein on the cell surface of transiently transfected CO S-I cells and in growth plate chondrocytes derived from the affected i nfant suggests that proline 132 is critical for the receptor's intrins ic binding activity. These findings suggest that the Blomstrand form o f human short-limbed dwarfism arises from defective PTHR1 signaling in the developing cartilaginous skeleton.