2000 Global Researcher Conference Proceeding
March 10 - 12, 2000
| Conference: | 2000 Global Researcher Conference |
|---|---|
| Title: | Analysis of molecular mechanisms causing V2 vasopressin receptor dysfunction in four patients with X-linked nephrogenic diabetes insipidus |
| Authors: | Schulz, Angela; Schoneberg, Torsten |
| Institution: | University of Leipzig |
Characterization of the molecular defect causing X-linked nephrogenic diabetes insipidus (NDI) in four patients revealed three novel missense mutations (A165D, L274P, V290G) and a submicroscopic deletion of a 3.2-kb genomic fragment encompassing most of the V2 vasopressin receptor (AVPR2) coding sequence. By using a PCR-based strategy, we localized the breakpoints within the first intron and the 3’ region of the AVPR2 gene. The genomic sequence of the closely located C1 gene was not altered by this deletion. Additionally to the deletion, a four-base-pair insertion (CAGT) was found between both breakpoints. All patients had a history of polyuria and polydipsia and the diagnosis of NDI was based on the lack of increase in urinary osmolality after administration of dDAVP. Two patients (L274P and 3.2-kb deletion) displayed severe forms of hydronephrosis, hydroureters and enlarged trabeculated bladder. Additionally to the classical phenotype of NDI, one patient presented with a unilateral inner ear defect. The combination of congenital NDI and deafness appears to be rare and was reported as congenital deafness and Meniere-type hearing loss.
Mutations of the AVPR2 gene result in receptor malfunction at different levels such as complete gene deletion, improper mRNA splicing, intracellular receptor retention, or disturbances in receptor-ligand binding. In order to functionally characterize the missense mutations found in our patients, mutant AVPR2s were transiently expressed and analyzed in cAMP accumulation assays and ELISA studies. Based on our functional data and their localization within the transmembrane receptor core, an interference with proper receptor assembly is assumed.
Schulz and Schöneberg analyzed the mutant vasopressin-2 receptors (AVPR2) of four NDI patients. One of the patients also had a unilateral inner ear defect. They found three mutations that had not been previously recorded and one mutation that deleted most of the AVPR2 coding sequence.
Different mutations in the AVPR2 gene result in different structural defects in the resultant AVPR2 proteins. And these differing structural defects result in differing functional defects such as complete gene deletion, improper mRNA splicing, the inability to transport to the cell membrane, or the inability to bind to arginine vasopressin (AVP).