Patients with diabetes insipidus (DI) present with persistent thirst, polydipsia, and hypotonic polyuria. The disorder is caused by several distinct etiologies and an appropriate diagnostic work-up is essential for the distinction of the various forms that include neurohypophyseal, nephrogenic, gestational, and polydipsic DI, which is also referred to as primary polydipsia. A complete, properly performed fluid deprivation/DDAVP test permits establishing the correct diagnosis. Several genetic forms of DI have been characterized at the molecular level during the last two decades. The neurohypophyseal form is caused by mutations in the AVP-NPII gene located on chromosome 20p13, which encodes the antidiuretic hormone vasopressin (AVP), and is usually inherited in an autosomal dominant fashion. Clinically, the deficiency in AVP secretion becomes apparent several months to years after birth and progresses in severity from partial to nearly complete. The postnatal progression is explained by degeneration of the AVP producing magnocellular neurohypophyseal neurons due to intracellular retention and a cytotoxic effect of the mutated precursor. The progressive deficiency in AVP is typically accompanied by the disappearance of the posterior pituitary bright spot signal on T1- weighted magnetic resonance imaging. Rarely, the disorder is caused by biallelelic mutations in the region of the AVP-NPII gene that encodes the nonapeptide AVP. We have identified a novel form of neurohypophyseal DI that is inherited in an X-linked recessive manner, and have established linkage to an ~8 centiMorgan interval on Xq28. This form of neurohypophyseal DI can not be explained by mutations in the AVP-NPII gene. The experiments outlined in this proposal aim at refining the linked region and to submit the candidate region to sequence analysis using a high-throughput approach. The results of this study are expected to provide novel fundamental insights into processing of AVP and thereby the physiology of water metabolism in humans.
Narrative Summary Normal water balance is essential for a normal function of the body and includes retention of water in the kidney, which is, in part, regulated by a hormone called anti-diuretic hormone (ADH), or vasopressin (AVP). We have identified a family with several males who lack this hormone and therefore void very large volumes of urine. This proposal aims at finding the underlying genetic defect because understanding of the defect at the molecular level could provide important insights into normal and abnormal water metabolism in humans.
| Bianco, Antonio C; Anderson, Grant; Forrest, Douglas et al. (2014) American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24:88-168 |
| Babey, Muriel; Kopp, Peter; Robertson, Gary L (2011) Familial forms of diabetes insipidus: clinical and molecular characteristics. Nat Rev Endocrinol 7:701-14 |
