Analysis of the P3 promoter of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene in pseudohypoparathyroidism type 1b

Hypocalcemia and hyperphosphatemia caused by PTH resistance are the only di scernible abnormalities in pseudohypoparathyroidism type Ib (PHP-1b). Becau se of the selective resistance toward PTH, inactivating mutations in its re ceptor, the PTH/PTH-related peptide receptor (PTHR1), were thought to be re sponsible for PHP-1b. However, gene abnormalities responsible for PHP-lb ha ve not been identified in the coding region and well conserved promoters (P 1 and P2) of the PTHR1 gene. The purpose of the present study was to analyz e the structure of the P3 promoter, the main promoter of the human PTHR1 ge ne in kidney, in patients with PHP-1b. Southern analysis of genomic DNA fro m lymphoblastoid cell lines of eight nonfamilial patients with PHP-1b revea led neither gross rearrangements nor methylation abnormalities in the P3 pr omoter region of the PTHR1 gene. Sequencing revealed no abnormalities in th e P3 promoter region, although one patient was homozygous for an (AAAG)n po lymorphic variant. In conclusion, despite the selective resistance toward PTH in the kidney, w hich mainly uses the PTHR1 P3 promoter, PHP-1b in eight cases is not associ ated with structural abnormalities in this promoter. This study also indica tes that inactivation of the P3 promoter is not achieved by methylation as tested in patients' genomic DNA from lymphoblastoid cell lines. The influen ce of alterations in the polymorphic A-rich repeat sequence on promoter act ivity warrants further study.