STUDIES ON PSEUDOHYPOPARATHYROIDISM AND RELATED DISORDERS

Project: Research project

Project Details

Description

In 1942 Albright and his associates described the features of a new
clinical syndrome "pseudohypoparathyroidism" (PHP). Patients with
his disorder differ from those with idiopathic hypoparathyroidism:
they show characteristic constitutional features (Albright's
hereditary osteodystrophy - AHO) and do not respond to exogenous
parathyroid hormone (PTH). Subsequent to the original report,
patients lacking the typical somatic features of AHO but resistant
to endogenous and administrated PTH have been described. In PHP,
UcAMP (urinary cyclic AMP) does not increase normally in response
to PTH administration. This indicated that there is a defective
hormone receptor-adenylate cyclase complex in this disorder. We
have now shown that many patients with PHP+AHO (PHP Ia) show an
approximately 50% reduction in activity of Gs (the stimulatory
guanine nucleotide binding protein associated with adenylate
cyclase) in membranes from multiple tissues. Gs deficiency
presumably accounts for resistance to multiple hormones in such
patients. Patients with PHP without AHO show normal Gs activity
(PHP Ib) and resistance only to PTH, and preliminary studies
suggest a PTH receptor defect in such patients. Rare patients with
PHP and AHO and multiple hormone resistance show normal Gs
activity.

Using cloned human cDNA probes for the alpha subunit of Gs, we now
find that steady state mRNA levels from fibroblasts of subjects
with PHP Ia are reduced by approximately 50% compared with normals.
Genomic cloning and other molecular biologic approaches are being
used to define the genetic abnormality responsible for Gs
deficiency in PHP Ia.
StatusNot started

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Genetics

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