Intrafamilial Phenotype Variability in Nephrogenic Diabetes Insipidus

Title: Intrafamilial Phenotype Variability in Nephrogenic Diabetes Insipidus
Authors: Kalenga, Karine; Persu, Alexandre; Goffin, Eric; Lavenne-Pardonge, Edith; van Cangh, Paul J.; Bichet, Daniel G.; Devuyst, Oliver
Publisher: American Journal of Kidney Diseases
Date Published: April 01, 2002
Reference Number: 553
X-linked nephrogenic diabetes insipidus (NDI), which accounts for 90% of inherited cases of NDI, is caused by mutations in the AVPR2 gene that encodes the arginine vasopressin (AVP) receptor type 2 (V2R). The V2R mediates the antidiuretic action of AVP in principal cells of the collecting duct. To date, only three AVPR2 mutations (P322S, D85N, and G201D) have been associated with a mild NDI phenotype, and intrafamilial phenotype variability has not been reported in affected males. We describe a novel Belgian family with X-linked NDI caused by substitution of a histidine for an arginine at position 137 (R137H) of AVPR2. This mutation has been identified in two brothers and their mother. The R137H mutation results in a failure of V2R to stimulate adenylate cyclase and has been associated consistently with severe NDI and the inability to increase urinary osmolality to greater than plasma osmolality during water deprivation and/or infusion of 1-desamino-8-d-arginine vasopressin. Detailed examination of the two affected brothers showed the typical NDI phenotype in the 45-year-old proband, whereas a milder clinical phenotype associated with significant urinary concentrating ability during water deprivation was documented in the 33-year-old brother. Thus, in this family, the R137H mutation is associated with either a mild or severe NDI phenotype. Mechanisms that might account for these findings include genetic and/or environmental modifiers. Copyright 2002 by the National Kidney Foundation, Inc.

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)

Ninety per cent of the cases of congenital nephrogenic diabetes insipidus (NDI) are due to mutations of the vasopressin-2 receptor (V2R) gene. Currently, over 155 different NDI causing mutations of the V2R gene have been reported. Of these, only three result in a mild expression of NDI symptoms. All the rest are associated with severe thirst and excessive voiding of dilute urine.

Kalenga, et al., studied a Belgian NDI family which was unusual in the respect that though two of the male siblings had the same V2R gene mutation, the older, a 45-year-old, had severe NDI symptoms and the younger, a 33-year-old, had mild ones. (The mother carried the same mutation, but was symptom free, as most female carriers are.) The older brother was mentally retarded, probably due to periods of dehydration in infancy as a result of NDI. He could not obtain stable employment and had an unsatisfactory social life. The younger brother had stable employment and a normal social life. During a water deprivation test, the older brother still could not concentrate urine, and injections of synthetic vasopressin (DDAVP) did not decrease his urinary output, whereas the younger brother was able to increase the concentration of his urine and did decrease his urinary output after DDAVP.

Their mutations (called R137H because it results in a histidine amino acid residue being in the position where an arginine residue should be) causes affected vasopressin-2 receptor proteins to be unable to reach the cell surface, where they must be to fulfill their function. It also reduces the V2R protein's ability to stimulate a major portion of the molecular sequence that leads to the kidney's ability to concentrate urine.

The R137H mutation has consistently been associated with severe NDI symptoms in people expressing the mutations. The researchers suggest that the milder symptoms of the younger brother could be due either to some modifying circumstances in the younger brother's V2R gene or variants in other genes involved in the urine-concentrating pathway. They also suggest that the consequences of NDI can be mitigated by early diagnosis along with proper treatment and pertinent information, and perhaps this accounted for the different outcomes in the brothers.