Patients with Autosomal Nephrogenic Diabetes Insipidus Homozygous for Mutations in the Aquaporin 2 Water-Channel Gene

Title: Patients with Autosomal Nephrogenic Diabetes Insipidus Homozygous for Mutations in the Aquaporin 2 Water-Channel Gene
Authors: van Lieburg, Angenita; Verdijk, Marian A.J.; Knoers, Nine; van Essen, A.J.; Proesmans, W.; Mallmann, Rudolf; Monnens, Leo A.H.; van Oost, Bernard A.; van Os, Carel; Deen, Peter M.T.
Publisher: American Journal of Human Genetics
Date Published: October 01, 1994
Reference Number: 88
Mutations in the X-chromosomal V2 receptor gene are known to cause nephrogenic diabetes insipidus (NDI). Besides the X-linked form, an autosomal mode of inheritance has been described. Recently, mutations in the autosomal gene coding for water-channel aquaporin 2 (AQP2) of the renal collecting duct were reported in an NDI patient. In the present study, missense mutations and a single nucleotide deletion in the aquaporin 2 gene of three NDI patients from consanguineous matings are described. Expression studies in Xenopus oocytes showed that the missense AQP2 proteins are nonfunctional. These results prove that mutations in the AQP2 gene cause autosomal recessive NDI.
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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)

The most common form of congenital nephrogenic diabetes insipidus is the X-linked recessive form. Here, the mutated gene that causes NDI, the arginine vasopressin receptor (AVPR2) gene, is located on the X chromosome. It is carried by females (who generally do not express the disorder) and it can be passed on to both son and daughter. However, generally only the son, if he inherits the defective gene from his mother, will express symptoms of the disorder. Scientists suspected there was another way NDI can be inherited, and that is through the transmission of a mutated aquaporin-2 gene. Aquaporin-2 (AQP2) is responsible for making the principal cells of the kidney collecting duct and inner medulla more water permeable. This allows the kidney to concentrate urine and maintain body water balance. When the kidney cannot perform this function, the result is NDI.

The AQP2 gene is carried on chromosome 12, a non-sex hormone. This means it can be carried by both males and females. A non-sex chromosome (and there are 22 of them) is called an autosome, and when a gene on an autosome is passed on to an offspring, it is called an autosomal mode of inheritance. vanLieburg, et al., analyzed three NDI patients and found that all three had mutations in both alleles of their AQP2 genes. (Each gene comes in pairs, one inherited from the mother and one inherited from the father. The form of a gene is called an allele. So in the case of the three NDI patients, both alleles of the AQP2 gene, the allele inherited from the mother and the allele inherited from the father, were mutated. When this is the case, the person is said to be homozygous for the mutation. They possess a pair of identical alleles at this location. And in this case, the alleles have the same mutation.)

Two of the patients had missense mutations, which means there is a change in one of the codons (a set of three contiguous bases that make up part of the gene). Since each codon is responsible for manufacturing a single amino acid, a mutated codon will synthesize a different amino acid than is required by the AQP2. This will change the structure (and often the ability to function) of the gene.

The third patient had a single deletion of one of the bases that made up the gene. (There are four of them, adenine (A), cytosine (C), guanine (G), and thymine (T), and they combine in many ways to form the gene's sequence. For example, a small part of one sequence may be AGTGCGAGAGCGAGT. If one of the bases is missing, it will change the sequence and thus change the structure of the gene. This change could render the gene non-functional, as in the case of this NDI patient.

The authors cloned the missense mutated genes and injected them into laboratory cell cultures. They wanted to see if the mutated genes would perform the function of normal AQP2s, which is to make the cell membranes more water permeable than normal so more water can flow through them. As expected, none of the mutated genes were functional. This proved that mutations in the AQP2 gene cause autosomal recessive NDI.