Molecular Biology of Diabetes Insipidus
| Title: | Molecular Biology of Diabetes Insipidus |
|---|---|
| Authors: | Fujiwara, T. Mary; Morgan, Kenneth; Bichet, Daniel G. |
| Publisher: | Annual Review of Medicine |
| Date Published: | January 01, 1995 |
| Reference Number: | 78 |
The identification, characterization, and mutational analysis of three different genes, namely the prepro-arginine-vasopressin-neurophysin II gene (prepro-AVP-NPII), the arginine-vasopressin receptor 2 gene (AVPR2), and the vasopressin-sensitive water channel gene (aquaporin-2, AQP2), provide the basis for our understanding of three different hereditary forms of diabetes insipidus: autosomal dominant neurogenic diabetes insipidus, X-linked nephrogenic diabetes insipidus, and autosomal recessive nephrogenic diabetes insipidus, respectively. These advances provide diagnostic tools for physicians caring for these patients.
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)
- A deficient secretion from the hypothalamus of the antidiuretic hormone, arginine vasopressin (AVP). This is the most common form of DI and is called neurogenic(or central or hypothalamic) DI.
- The kidneys do not respond to the message of the antidiuretic hormone, AVP. This form of DI is called nephrogenic DI (NDI).
- For some reason, the patient, to satisfy no valid physiologic need, habitually consumes large volumes of water. This is called primary polydipsia.
The less mature forms of AVP and neurophysin II (NPII), the molecular structure that carries AVP through the body, are synthesized in the hypothalamus. These forms are transported to the pituitary, and along the way they become the mature forms of AVP and NPII. The gene responsible for the synthesis of AVP and NPII is called the prepro-arginine-vasopressin-neurophysin II gene (prepro AVP-NPII), and mutations in it are responsible for neurogenic DI. Mutated genes can produce faulty proteins (and hence the molecular structures which they build, such as, in this instance, AVP and NPII). Mutated AVP and NPII do not behave normally. For example, they could be non-functional, or they could function when they are not supposed to. In any case, the AVP is not capable of telling the body to concentrate urine. Though inherited, the symptoms of neurogenic DI do not show up in infancy.
Even if the AVP is healthy, it still needs other molecular structures to function normally if the body is to concentrate urine properly. Normally, AVP will bind to an arginine-vasopressin type 2 receptor (V2 receptor). The receptor, responding to a signal from AVP, continues a process that results in the kidney concentrating urine. The V2 receptor gene is responsible for synthesizing the V2 receptor and, if it is mutated, it can produce faulty V2 receptors that do not respond to AVP and therefore prevent the kidney from concentrating urine. When this occurs, NDI occurs.
One form of NDI is called X-linked NDI because the mutated gene is located on the X chromosome. In this form of inheritance, the female carries the mutant gene, but does not generally display the disorder. However, should her son inherit the mutated gene from her, he will express the disorder. This is because females have two X chromosomes and males have only one. Almost every protein in the body has two genes capable of producing it, one that is inherited from the mother and one that is inherited from the father. Both genes are located at the same site on each of a pair of chromosomes and though considered a pair or partners, the genes may or may not be identical. If one of these genes mutates or is mutated, it could produce an altered protein. But often the presence of a mutated gene is masked by its normal partner gene. So, most genes each have a partner carried next to it at the same location on a chromosome. If one of the genes masks the effects of its partner, it is said to be dominant, whereas the masked gene is said to be recessive. Since males have only one X chromosome, the genes carried on it (such as the V2R gene) do not have another V2R gene pair to mask it should it be mutated.
X-linked NDI is recessive. NDI normally affects males, though females carry the defective gene on their X-chromosome and pass it on to their sons. Sixty-three DI-causing mutations of V2 receptor genes have been reported in 90 unrelated families from diverse ethnic groups. Symptoms of NDI can occur the first week of life. They include polyuria, excessive thirst, dehydration, constipation, fever, anorexia and failure to thrive. If undiagnosed and untreated, NDI-induced dehydration could result in physical and mental retardation.
Part of the urine concentrating process involves a water-transporting protein called aquaporin-2 (AQP2). When signaled to do so by AVP, AQP2 travels to specific kidney cell membranes in order to make them much more water permeable. The gene that synthesizes AQP2 is called the AQP2 gene. If it is mutated, the AQP2 is unable to perform its function. Thus mutations of the AQP2 gene are another cause of NDI. The AQP2 gene is located on an autosomal chromosome, which means that both males and females are susceptible to this inherited form of NDI.
That three separate genes that cause DI have been identified, allowing for early diagnosis and management of at-risk members of families who have previously shown NDI in their lineage. Since NDI manifests in the first weeks of life, early diagnosis is crucial for normal development of the patient. Knowledge of defects in the antidiuretic hormone, the V2 receptor, and the water-transporting protein due to mutations in the prepro-AVP-NPII, V2 receptor and AQP2 genes, respectively, will hopefully further the ability to treat and perhaps one day, cure DI.