Project: Research project

Project Details


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 severe
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 determined 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
one family thus far have identified a mutation 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


  • Endocrinology, Diabetes and Metabolism
  • Genetics


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