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Inactivating Mutation in the Human Parathyroid Hormone Receptor Type 1 Gene in Blomstrand Chondrodysplasia

Division of Endocrinology (A.C.K., B.H., M.T.A.N.), Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital and Lady Davis Institute for Medical Research, McGill University, Montréal, Canada H3T 1E2; Department of Clinical Genetics (I.D.Y.), City Hospital, Nottingham, United Kingdom; Department of Histopathology, Derbyshire Royal Infirmary, NHS Trust, Derby, United Kingdom (D.S.); and 1st Department of Oral Anatomy (H.O., N.A.), Nigata University School of Dentistry, Niigata, Japan

Address all correspondence and requests for reprints to: Andrew C. Karaplis, M.D., Ph.D., McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Lady Davis Research Institute, Room 626 3755 Cote Ste Catherine Road, Montréal, H3T 1E2, Canada.

A single homozygous nucleotide exchange in exon E3 of the gene encoding the parathyroid hormone receptor type 1 (PTHR1) was identified in an infant with Blomstrand chondrodysplasia born to consanguineous parents. This alteration changes a strictly conserved proline residue at position 132 in the receptor’s amino terminal extracellular domain to leucine. COS-1 cells expressing the mutant receptor did not accumulate cyclic adenosine 3',5'-monophosphate in response to PTH or PTH-related peptide (PTHrP) and did not bind the radiolabeled ligand. Expression of the mutant protein on the cell surface of transiently transfected COS-1 cells and in growth plate chondrocytes derived from the affected infant suggests that proline 132 is critical for the receptor’s intrinsic binding activity. These findings suggest that the Blomstrand form of human short-limbed dwarfism arises from defective PTHR1 signaling in the developing cartilaginous skeleton.

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