1998 Global Conference Proceeding
March 02 - 04, 1998
| Conference: | 1998 Global Conference |
|---|---|
| Title: | The Medical Geneticist's Perspective on NDI Research |
| Author: | Wildin, Robert |
| Institution: | (formerly) Oregon Health Sciences University, MP350 |
Nephrogenic diabetes insipidus (NDI) is an inborn error of water homeostasis that presents in early infancy. It is caused by a genetically determined failure of arginine vasopressin (AVP) signal transduction in the distal tubule and collecting duct. A family in which a diagnosis of NDI has been made may have several questions about the genetic aspects of the disease. Scientific and technical advances are now capable of answering many of these questions.
The X-linked AVPR2 gene encodes the type 2 vasopressin receptor. This laboratory has detected 34 different AVPR2 alleles with sequence variations among 36 unrelated NDI patients. Two of the patients are female.
In more than half of the families, there was no prior family history of NDI. Thus, the vast majority of new NDI patients have the X-linked form of NDI rather than the autosomal form due to aquaporin-2 defects. Mutation detection methods can confirm a clinical diagnosis and establish the expected inheritance pattern. A confusing clinical picture in partially affected females can be clarified by searching for a mutation in AVPR2. Once a mutation is detected in a family, other family members at risk for being carriers, or newborn males, may be tested to determine their genetic status. Direct mutation analysis is more accurate than linkage analysis, and, since new mutations are not uncommon, it has the advantage of being able to rule out carriage in the mother or aunt of an affected boy.
Seventeen of the variant AVPR2 receptor genes have been analyzed for residual function in this lab. Several of them express receptors with residual responsiveness to high doses of AVP, although most are non-functional when expressed in human cells in culture. The clinical relevance of this finding is uncertain, but functional analysis is important for genetic counseling because a missense mutation may represent an insignificant polymorphic change rather than one causing disease. Studying these variant vasopressin receptors may also imply how the function of this particular receptor is related to its structure, a scientific question whose answer may be extrapolated to the huge super-family of G protein-coupled receptors.
As a recessive genetic disease, NDI could theoretically be cured by replacing the defective gene, i.e. gene therapy. This exciting prospect would eliminate lifelong, often inadequate management with thiazide diuretics. The many obstacles to gene therapy for NDI may be surmountable with a coordinated multidisciplinary approach.
Scientific advances have provided some answers into the genetic nature of nephrogenic diabetes insipidus (NDI). The vast majority of NDI cases are due to mutations in the X-linked AVPR2 gene. That is, the mutation occurs in a sex chromosome which means that mostly males are affected. Another, much less frequent, form of NDI is due to a mutation in the aquaporin-2 gene located on an ordinary paired chromosome, alike in males and females. The author's laboratory has detected 34 different types of mutations in the AVPR2 gene among 36 unrelated NDI patients, two of whom are female. Since scientists are now able to detect mutations associated with NDI, they can confirm clinical diagnoses of NDI as well as establish the expected family inheritance pattern. Thus, once an NDI mutation is detected in a family, other family members can find out if they are carriers of the mutation, and newborns can be immediately tested for NDI-related mutations so they can receive proper treatment immediately.
Wildin's laboratory studies the function as well as the structure of the mutated AVPR2 receptor genes because on rare occasions a variant shape (i.e., a mutation) may not lead to a significant functional change (i.e., the receptor can still do its job). Studying how this gene's function is related to its structure could provide insight into many other types of receptors necessary for a healthy body. Further multidisciplinary advances in the genetic understanding of NDI could produce the knowledge and skill necessary to replace a patient's defective genes with fully-functioning genes, thus providing a cure for those suffering from NDI.