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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

Cristina Boccalandro^*, Fabrizio de Mattia, Dong-Chuan Guo, Li Xue, Philip Orlander^*, Terri M. King, Prateek Gupta, Peter M.T. Deen, Victor R Lavis^* and Dianna M. Milewicz

*Division of Endocrinology and Division of Medical Genetics, University of Texas Houston Medical School, Houston; and Department of Cell Physiology, University of Nijmegen, Nijmegen, The Netherlands.

Correspondence to Dr. Dianna M. Milewicz, University of Texas Medical School at Houston, 6431 Fannin, MSB 1.614, Houston, TX 77030. Phone: 713-500-6727; Fax: 713-500-0693; E-mail: Dianna.M.Milewicz{at}uth.tmc.edu

ABSTRACT. 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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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673