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 blotting and
other molecular biologic approaches are being used to define the genetic
abnormality responsible for Gs deficiency in PHP Ia.
StatusNot started

ASJC

  • Genetics