Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family: Evidence of Increased Frequency of the Mutation in the Town of Origin

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Title: Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family: Evidence of Increased Frequency of the Mutation in the Town of Origin
Authors: Boccalandro, Christina; de Mattia, Fabrizio; Guo, Dong-Chuan; Xue, Li; Orlander, Philip; King, Terri M.; Gupta, Prateek; Deen, Peter M.T.; Lavis, Victor R.; Milewicz, Dianna M.
Publisher: Journal of American Society of Nephrology
Date Published: May 01, 2004
Reference Number: 648
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A Mexican family with partial congenital nephrogenic diabetes insipidus (NDI) that resulted from a mutation in the aquaporin-2 water channel (AQP2) was characterized, and the source of this rare mutation was traced to the family's town of origin in Mexico. Affected individuals with profound polyuria and polydipsia were homozygous for an autosomal recessive missense V168M mutation in the AQP2 gene. Expression in oocytes revealed that, although retained in the endoplasmic reticulum (ER) to a great extent, a considerable amount of the partially functional AQP2-V168M was expressed at the plasma membrane, and that its ER retention was less than AQP2-T126M, a functional mutant in severe recessive NDI. None of the affected AQP2-V168M individuals had neurologic deficits, which also suggested a milder form of the disease. The homozygous individuals reported subjective improvement in polyuria and polydipsia with the use of dDAVP (1-desamino-8-D-arginine-vasopressin). When clinically tested, infusion of dDAVP at variable doses produced a partial increase in the urinary osmolality in homozygous individuals and decreased their water intake. Heterozygotes were unaffected when compared with controls. Samples were obtained from the population of the Mexican town of origin of the family; 30% of the population was heterozygous for the V168M AQP2 mutation and 1% was homozygous for the mutation. The high frequency of this rare mutation in the town provides evidence for an important health care problem in the village with consequences for future generations.
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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)

Congenital NDI generally results from a mutation of the vasopressin 2 receptor (V2R) gene or the aquaporin 2 (AQP2) gene. Though the vast majority of NDI causing mutations are found in V2Rs, thirty mutations of AQP2 have been reported. Most of these AQP2 mutations result in AQP2 proteins that are misshapen and therefore held in the endoplasmic reticulum (ER), the quality control center of the cell. Thus, mutant AQP2s are unable to travel to the cell membrane where they must be if they are to perform their function.

Boccalandro, et al., discovered a new AQP2 mutation: AQP2-V168M. This mutation is inherited in a recessive manner, which means both biological parents must have a mutant AQP2 gene. The research team was able to discover and describe how AQP2-V168M malfunctions and gives rise to NDI. They were also able to trace the source of the mutation to a small Mexican town.

AQP2-V168M results in a form of NDI that is not as severe in its effects as usual because AQP2-V168M is partially functional. That is, like most mutant AQP2, a large number of AQP2-V168M are retained in the ER. However, enough of the partially functional mutant is able to travel to the cell membrane to let water enter the cell. Normally, treatment with dDAVP, a synthetic analog of the hormone, arginine vasopressin (AVP) has no effect on NDI patients because NDI is not due to lack of AVP. However, the people with NDI due to AQP2-V168M did experience a reduction in the severity of their NDI symptoms. They experience reduced thirst and urine output and more concentrated urine.

Tracing the origin of this mutation back to a small Mexican town, the researchers found that 30% of the population carried the AQP2-V168M gene mutation on one of their chromosomes. Since a person must have the mutant gene on both chromosomes (inheriting the mutated gene from both mother and father) to express NDI, 1% of the town expressed NDI. However, since so many of the people of the town could pass the mutation on to their offspring, the researchers helped the local health care providers to have a deeper understanding of the problem.