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 this 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 administered 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
  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Genetics