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Selective Resistance to Parathyroid Hormone in Cultured Skin Fibroblasts from Patients with Pseudohypoparathyroidism Type Ib^*

SILVE CAROLINE, ARTHUR SANTORA, NEIL BRESLAU, ARNOLD MOSES and ALLEN SPIEGEL

Molecular Pathophysiology Section, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases,National Institutes of Health Bethesda, Maryland 20892;
University of Texas Health Science Center, Southwestern Medical School Dallas, Texas 75235;
State University of New York, Upstate Medical Center Syracuse, New York 13210

Address all correspondence and requests for reprints to: Allen M. Spiegel, National Institutes of Health, Building 10, Room 9C101, Bethesda, Maryland 20892.

We measured cAMP production in response to agonists in cultured skin fibroblasts from subjects with pseudohypoparathyroidism type Ib (PHP Ib; normal phenotype, resistance to PTH only, normal guanine nucleotide stimulatory coupling protein activity) and skin fibroblasts from normal subjects. There were no significant differences in basal or prostaglandin E₁- and forskolin-stimulated cAMP production in PHP Ib vs. normal fibroblasts. Fibroblasts from 7 of 10 subjects with PHP Ib had significantly reduced peak cAMP responses to PTH [3.95 ± 0.88 vs. 15.9 ± 4.2 pmol/100 g protein (mean ± SD); n = 7 for both groups; P < 0.001]. PTH-stimulated cAMP production was significantly reduced in the 7 subjects with PHP Ib at all concentrations of PTH tested [3–1000 ng/ml human PTH-(1–34)]. In the other 3 subjects with PHP Ib, the cAMP response to PTH was either normal (2 subjects) or above the normal range (1 subject). Thus, skin fibroblasts from many, but not all, subjects with PHP Ib have selective resistance to PTH in terms of cAMP response. Since the defect is hormone specific and persists in culture, we suggest that an intrinsic defect in the PTH receptor may cause PTH resistance in certain subjects with PHP Ib. The cause of PTH resistance in the subjects with a normal cAMP response to PTH is not known, but the data suggest heterogeneity even within the PHP Ib subgroup.

^* This work was supported in part by Grants RR-229 (Syracuse) and RR-00633 (Dallas) from the General Clinical Research Center Program of the Division of Research Resources, NIH, and NIH Grant AM-26253 (to N.B.).

Present address: CNRS ER126, Hopital Necker, 149 rue de Sevres,75015 Paris, France.

Received July 5, 1985.

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