CLONING AND CHARACTERIZATION OF THE PROMOTER REGIONS OF THE HUMAN PARATHYROID-HORMONE (PTH) PTH-RELATED PEPTIDE RECEPTOR GENE - ANALYSIS OFDEOXYRIBONUCLEIC-ACID FROM NORMAL SUBJECTS AND PATIENTS WITH PSEUDOHYPOPARATHYROIDISM TYPE 1B

Expression of the PTH/PTH-related peptide (PTHrP) receptor (PTHR) in t he mouse is controlled by at least two promoters. The downstream promo ter (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, pseudohy poparathyroidism type Ib (PHP1b), in which renal, but not osseous, sig naling by PTH is defective. We, therefore, cloned and characterized th e 5'-end of the human PTHR gene and found that its organization is ver y similar to that of the mouse. Transcription initiation sites of huma n 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 PHP 1b patients did not reveal any rearrangements in proximal promoter reg ions or exons encoding 6'-untranslated region sequences. No significan t 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 selectio n, stability, or splicing of renal PTHR transcripts. These data indica te that the genetic defect(s) in PHP1b in these patients lies in dista l enhancer elements of the gene, in an essential transcriptional regul ator, or in some as yet unidentified cofactor required for renal PTH s ignaling.