Pseudohypoparathyroidism (PHP) is a heterogeneous disease complex characterized by resistance to parathyroid hormone (PTH). PHP type Ib has been thought to be caused by abnormalities in PTH/PTH-related protein (PTHrP) receptor. However, previous studies have shown no mutation in the coding region of PTH/PTHrP receptor gene in patients with PHP type Ib. Because patients with PHP type Ib do not have Albright's hereditary osteodystrophy, and because resistance to PTH is most prominent in proximal tubules of the kidney, PHP Ib may be caused by a kidney-specific abnormality in PTH/PTHrP receptor. Cloning of 5' region of human PTH/PTHrP receptor gene revealed that there are at least three untranslated exons, U1, U2 and U3. Exons U1 and U2 and the upstream promoter of exon U1 are used in kidney, but not in skin fibroblasts and osteoblastic cells. The upstream region of exon U1 was highly AT-rich and exhibited kidney-specific promoter activity. However, there was no mutation in these kidney-specific promoter regions and untranslated exons in eight patients with PHP type Ib. These results demonstrate that PHP type Ib is not caused by mutations in PTH/PTHrP receptor gene, at least in the examined patients. Identification and characterization of nuclear proteins that bind to kidney-specific promoter region of human PTH/PTHrP receptor may be necessary for the elucidation of pathogenesis of PHP type Ib.