STUDIES ON NEPHROGENIC DIABETES INSIPIDUS

Project: Research project

Project Details

Description

Nephrogenic diabetes insipidus (NDI) is an inherited X-linked disorder
in which affected subjects are resistant to the actions of vasopressin
(AVP) on renal medullary cells responsible for water concentration.
Clinical manifestations include severe polydipsia and polyuria, and
resultant sever dehydration can lead to cerebral swelling and death.
Treatment with a potent AVP analog (DDAVP), useful in other forms of DI,
is ineffective in NDI because of end organ resistance to the hormone.
The renal actions of AVP are mediated through a V2 type receptor linked
via the Gs protein to stimulation of the 2nd messenger cAMP. In theory,
the inherited gene defect could be located anywhere along the signal
transduction path, but indirect evidence suggested a likely receptor
defect. The recent cloning of a human V2 receptor permitted chromosomal
localization studies which showed that the receptor is localized to Xq28,
the site of the gene defect as determine by family linkage studies. This
strongly suggested but did not prove that a receptor gene mutation is the
underlying defect in NDI. We have obtained genomic DNA samples on
multiple families with NDI, and in eight families thus far have
identified mutations predicted to disrupt formation of a normal V2
receptor. These findings have important implications for our
understanding of the pathogenesis of NDI and of normal V2 receptor
structure and function, for identification of affected subjects and
carriers, and eventually for gene therapy of the disease.
StatusNot started

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Endocrinology, Diabetes and Metabolism

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