Diabetes Insipidus (Hendy, Bichet)
| Title: | Diabetes Insipidus (Hendy, Bichet) |
|---|---|
| Authors: | Hendy, PhD, Geoffrey N.; Bichet, Daniel G. |
| Publisher: | Baillieres Clinical Endocrinology and Metabolism |
| Date Published: | July 1995 |
| Reference Number: | 58 |
The advances in our understanding of the pathophysiology of defects in the antidiuretic hormone, the V2 receptor and the water channel, owing to mutations in the prepro-AVP-NPII, AVPR2 and AQP2 genes respectively, is providing insight into inherited diabetes insipidus as well as the more numerous sporadic cases. Further structure-function analyses of these mutated genes will increase our understanding of normal vasopressin-regulated water transport across the kidney epithelium at the molecular level.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
- neurogenic diabetes insipidus, in which not enough of the antidiuretic hormone, arginine vasopressin (AVP) is produced or secreted by the hypothalamus.
- nephrogenic diabetes insipidus (NDI), in which the kidneys are insensitive to the antidiuretic signal of AVP.
- primary polydipsia, in which a chronic, excessive water intake by the patient suppresses the release of AVP from the hypothalamus.
The prepro-AVP-NP11 gene synthesizes the precursor form of AVP (which develops into AVP). mutations in this gene are associated with neurogenic DI. Different mutations result in different defects which alter the AVPs ability to function in different ways. In analyzing these mutations, researchers have attempted to see how the change in structure of the defective AVP synthesized by the mutated prepro-AVP-NP11 gene affects the AVPs ability to function.
There are also a variety of different mutations in the V2R gene (which is responsible for X-linked NDI) and, to a lesser but still significant extent, in the gene responsible for autosomal recessive NDI (the AQP2 gene). To date, more than 60 different mutations have been identified in the V2R gene. These mutations have been found in every part of the V2R gene and these different mutations affect the V2Rs structure, and therefore their ability to function, in different ways. Some of these mutations cause the V2R to not develop its tail (you can look at a representation of the V2R here). This results in non-functional receptors unable to travel to their work site on the cell membrane of the principal cells of the kidney collecting duct.
Other V2R gene mutations produce V2Rs that have a diminished ability to stimulate parts of the molecular sequence (such as adenylyl cyclase) that is responsible for the kidney being able to reabsorb water and concentrate urine. Other mutations produce V2Rs with structural defects that do not let them properly contact the Gs protein, which is essential for urine concentration. And other mutations result in V2Rs with multiple functional defects. The same is true for mutations of the AQP2 gene, though there are far fewer cases of NDI caused by AQP2 gene mutations and far fewer mutations identified in comparison to NDI caused by V2R gene mutations.
The authors note how advances in the molecular biology of NDI allow clinicians to distinguish between NDI caused by V2R gene mutations and AQP2 gene mutations, and how they allow for immediate post-natal diagnoses of suspected NDI patients. As NDI can manifest in the first days of life, early knowledge of it allows proper treatment which can avoid the possibly severe consequences of the untreated disorder.
Researchers are hopeful that further research will enable them to develop effective therapeutic strategies for NDI, no matter what the cause.