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 this
disorder show characteristic constitutional features (Albright's
hereditary osteodystrophy - AHO) and do not respond to exogenous
parathyroid hormone (PTH). In PHP, UcAMP (urinary cyclic AMP) does not
increase normally in response to PTH administration. This indicates that
there is a defective hormone receptor-adenylate cyclase complex in this
disorder. We have 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. Using cloned human
cDNA probes for the alpha subunit of Gs, we have shown that steady state
mRNA levels from fibroblasts of subjects with PHP Ia are reduced by
approximately 50% compared with normals. We have now succeeded in
defining the genetic abnormality responsible for Gs deficiency. Using
the polymerase chain reaction, denaturing gradient gel electrophoresis
and direct sequencing, we were able to identify mutations that would
explain reduction in mRNA in affected subjects. Other patients express
renal resistance to PTH but no features of AHO or resistance to other
hormones. Previous work in this laboratory showed a selective resistance
of cAMP generation to PTH in fibroblasts from these patients, suggesting
a potential defect in the PTH receptor.
StatusNot started

ASJC

  • Genetics

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