2000 Global Researcher Conference Proceeding
March 10 - 12, 2000
| Conference: | 2000 Global Researcher Conference |
|---|---|
| Title: | Variations in clinical phenotype associated with different mutations of the V2 receptor gene in X-linked recessive congenital nephrogenic DI (xCNDI) |
| Authors: | Robertson, Gary; Kopp, M.D., Peter; Bichet, Daniel G. |
| Institutions: | Northwestern University Medical School, Northwestern University, Hopital du Sacre-Coeur de Montreal |
xrCNDI has been linked to a large number of different mutations in the gene encoding the receptor that mediates the biologic effects of the antidiuretic hormone, arginine-vasopressin (AVP). The mechanism(s) by which these diverse mutations interfere with V2 receptors has not been fully determined but in vitro expression studies suggest a variety of defects ranging from impaired production or intracellular trafficking to inefficient AVP binding or coupling to Gsa. The present study was undertaken to determine if differences in genotype also result in appreciable differences in the clinical phenotype. To this end, we characterized the abnormalities in antidiuretic function in 21 affected males from 14 apparently unrelated kindreds with 13 different mutations of the V2 receptor gene. Plasma AVP (Pavp) as well as plasma and urine osmolality (Pos and Uos) were measured hourly during a standard fluid deprivation test and the relationship between these 3 variables were compared among the patients and to 25 normal controls. We found that 15 patients from 11 kindreds with different mutations (G151Qfs, R202C, Q174L, S167W, W193X, S167L, R137H, V189fs210X, N321K, L292P and a large undefined deletion) all had severe defects in antidiuretic function since their Uos rose to maxima of only 60 to 260 mosmoles/kg even when their endogenous Pavp was increased to markedly supraphysiologic levels (20 to 80 pg/ml) by fluid deprivation. In these patients, the relationship of Uos to Pavp was either abnormally shallow or completely flat. However, in the other 5 patients from 3 kindreds with 2 different mutations (D85N, D85N and G201D), resistance to the antidiuretic effect of AVP was incomplete since their Uos rose as high as 390 to 595 mosmoles/kg when fluid deprivation increased their endogenous Pavp to 20 to 55 pg/ml. In these patients, the relationship of Uos to Pavp was shifted to the right of normal. In all 21 patients with xrCNDI, the relationship of Pavp to Pos was shifted to the left or above the normal range and this shift tended to be greater in those with severe rather than partial defects in V2 receptor function. These findings show that different mutations of the V2 receptor gene (1) result in markedly different degrees of resistance to the antidiuretic effect of AVP in vivo and (2) are invariably associated with unexplained, osmotically excessive increases in AVP secretion. This suggests that patients with mutations causing partial defects may be misdiagnosed by standard fluid deprivation tests and might be treated effectively with large doses of DDAVP or other V2 receptor agonists that lack V2 effects. They also raise the possibility that abnormally high endogenous Pavp levels acting unopposed at V1 receptors may effect other physiologic systems in patients with xrCNDI.
Researchers have found many different mutations of the arginine vasopressin 2 receptor (AVPR2) gene that result in congenital NDI. Different mutations of the AVPR2 gene result in different structural alteration of the AVPR2s expressed by the respective AVPR2 genes. This results in differing AVPR2 dysfunctions.
Robertson, et al., studied 21 males with X-linked NDI. There were 13 different AVPR2 gene mutations among these subjects. The researchers wanted to determine if different AVPR2 gene mutations resulted in appreciably different clinical expressions of X-linked NDI. To do this, the researchers measured the amount of arginine vasopressin (AVP) in their subjects' plasma (Pavp) as well as the concentration of osmotically active particles in their plasma (Pos) and urine (Uos). They measured these variables hourly while the subjects abstained from fluid.
Robertson, et al., found that 15 of the subjects (from 11 different families with each family having a different mutation) exhibited a severe inability to concentrate urine, as indicated by a persistently low Uos in the face of a marked rise in Pavp. However, five other subjects from three families with two different mutations showed a somewhat better ability to concentrate urine as they increased Uos to over 300 in response to their increase in Pavp.
These findings show that different mutations of the AVPR2 gene result in significantly different physical expressions of NDI and that each mutation is accompanied by excessive increases in the amount of AVP circulating in the blood. These findings suggest that NDI patients with less severe symptoms could be misdiagnosed by standard fluid deprivation tests and might be treated effectively with high doses of synthetically modified AVP. They also raise the question whether the chronic elevations in Pavp may act at normal AVPR1 receptors to affect other parts of X-linked NDI patients' bodies.