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Cloning and Characterization of the Promoter Regions of the Human Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene: Analysis of Deoxyribonucleic Acid from Normal Subjects and Patients with Pseudohypoparathyroidism Type 1b¹

Department of Physiology, McGill University (J.D.B., M.Y.K., H.S.L., G.N.H., D.G., J.H.W.), Montreal, Quebec, Canada H3G 1Y6; the Department of Medicine and Calcium Research Laboratory, McGill University and Royal Victoria Hospital (M.M., G.N.H., D.G.), Montreal, Quebec, Canada H3A 1A1; and the Department of Pediatrics, Chiba University School of Medicine (M.M., T.Y.), Inohana, Chuo-ku, Chiba, Japan

Address all correspondence and requests for reprints to: Dr. J. H. White, Department of Physiology, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada H3G 1Y6. E-mail: jwhite{at}physio.mcgill.ca

Expression of the PTH/PTH-related peptide (PTHrP) receptor (PTHR) in the mouse is controlled by at least two promoters. The downstream promoter (P2) is ubiquitously expressed, whereas expression of the upstream promoter (P1) is largely restricted to kidney. These observations may provide a genetic basis for a human PTH resistance syndrome, pseudohypoparathyroidism type 1b (PHP1b), in which renal, but not osseous, signaling by PTH is defective. We, therefore, cloned and characterized the 5'-end of the human PTHR gene and found that its organization is very similar to that of the mouse. Transcription initiation sites of human P1 and P2 promoters are in similar, but not identical, positions to those of the mouse gene. The identification of a human P2 promoter is significant because no P2-specific human PTHR complementary DNAs have been isolated to date. Southern analysis of genomic DNA from seven PHP1b patients did not reveal any rearrangements in proximal promoter regions or exons encoding 5'-untranslated region sequences. No significant sequence differences were found in clones of normal and patient DNAs encompassing proximal promoter sequences, and untranslated region and signal sequence exons. Thus, in the seven PHP1b patients analyzed, no defects were identified that would influence initiation site selection, stability, or splicing of renal PTHR transcripts. These data indicate that the genetic defect(s) in PHP1b in these patients lies in distal enhancer elements of the gene, in an essential transcriptional regulator, or in some as yet unidentified cofactor required for renal PTH signaling.

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