CLONING AND CHARACTERIZATION OF KIDNEY-SPECIFIC PROMOTER OF HUMAN PTHPTHRP RECEPTOR GENE - ABSENCE OF MUTATION IN PATIENTS WITH PSEUDOHYPOPARATHYROIDISM TYPE IB/

Pseudohypoparathyroidism (PHP) is a heterogenous disease complex chara cterized by resistance to parathyroid hormone (PTH). PHP type Ib has b een thought to be caused by abnormalities in PTH/PTH-related protein ( PTHrP) receptor. However, previous studies have shown no mutation in t he coding region of PTH/PTHrP receptor gene in patients with PHP type Ib. Because patients with PHP type Ib do not have Albright's hereditar y osteodystrophy, and because resistance to PTH is most prominent in p roximal tubules of the kidney, PHP Ib may be caused by a kidney-specif ic abnormality in PTH/PTHrP receptor. Cloning of 5' region of human PT H/PTHrP receptor gene revealed that there are at least three untransla ted 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 osteoblas tic cells. The upstream region of exon U1 was highly AT-rich and exhib ited kidney-specific promoter activity. However, there was no mutation in these kidney-specific promoter regions and untranslated exons in e ight patients with PHP type Ib. These results demonstrate that PHP typ e Ib is not caused by mutations in PTH/PTHrP receptor gene, at least i n the examined patients. Identification and characterization of nuclea r proteins that bind to kidney-specific promoter region of human PTH/P THrP receptor may be necessary for the elucidation of pathogenesis of PHP type Ib. (C) 1998 Elsevier Science Ireland Ltd. All rights reserve d.