Aquaporin-2 Water Channel Mutations and Nephrogenic Diabetes Insipidus: New Variations on a Theme

Title: Aquaporin-2 Water Channel Mutations and Nephrogenic Diabetes Insipidus: New Variations on a Theme
Authors: Rutishauser, Jonas; Kopp, M.D., Peter
Publisher: European Journal of Endocrinology
Date Published: February 01, 1999
Reference Number: 222
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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)

Aquaporins (AQPs) are a family of membrane proteins that act as water channels in cell membranes. That is, when inside the cell membrane they act as channels through which water can cross the cell membrane in greater volumes than it could in the absence of AQPs. There are different types of AQPs; nine that have been cloned are found in mammals. At least four of these AQPs are found in the kidney, aiding in water transport across cell membranes at different locations in the kidney. Three of these -- AQP2, AQP3 and AQP4 -- are located in the principal cells of the kidney collecting duct (CD).

AQP2 is regulated by the antidiuretic hormone, arginine vasopressin (AVP). When AVP binds with the vasopressin-2 receptor (located in the CD principal cell membrane) it initiates a molecular sequence which induces AQP2-bearing vesicles to travel to and fuse with the principal cell apical membrane. Once the vesicles fuse to the apical membrane, the AQP2s are inserted, leading to a dramatically increased amount of water that can cross the membrane. When AVP absents itself from the cell, the AQP2s are retrieved and taken back inside vesicles to again wait beneath the apical membrane. This process is what allows the kidney to reabsorb water passing through its CDs, leaving behind concentrated urine that is shunted to the bladder. Thus, AQP2 plays an important role in helping the kidney concentrate urine and maintain body water balance.

Congenital nephrogenic diabetes insipidus (NDI) is a disorder characterized by the kidneys' inability to respond to AVP. Therefore, the kidney cannot reabsorb water flowing through its CDs, concentrate urine, or balance body water. Most cases of congenital NDI are the result of mutations in the vasopressin-2 receptorgene, located on the X chromosome. In these cases, the disorder is inherited in an X-linked recessive pattern.

A minority of the cases of congenital NDI are caused by mutations of the AQP2 gene, located on chromosome 12. Most instances of NDI caused by this mutation are inherited in an autosomal recessive pattern. This means the mutation is carried on a non-sex hormone and that both parents must contribute a mutated AQP2 gene for their male or female infant to inherit the disorder.

However, very rarely, NDI caused by AQP2 mutations may be inherited in an autosomal dominant fashion. This means that only one parent need contribute a mutated AQP2 gene, and the baby will inherit the disorder. The authors report on one such instance of autosomal dominant inheritance of NDI. This was a mutation of the AQP2 gene that resulted in the substitution of a glutamic acid by lysine. Normally, glutamic acid is the 258th amino acid residue in the amino acid sequence that makes up the AQP2. In this mutation (Glu258Lys), lysine is at position 258 instead of glutamic acid.

This single amino acid substitution has severe functional consequences. Tests in laboratory cell cultures showed that Glu258Lys AQP2s could not get to the apical cell membrane because they were retained in a part of the cell called the Golgi apparatus. When these mutant AQP2s were expressed in the cell cultures along with normal AQP2s, both types were retained in the Golgi apparatus. This suggests that the dominant negative effect of the Glu258Lys mutant occurs through Golgi retention of AQP2s composed of mutant and normal AQP2 molecules.

This contrasts with the functional consequences of AQP2 mutations causing autosomal recessive NDI. With these, the tendency is for the AQP2 to be retained in another part of the cell called the endoplasmic reticulum (ER). In one study performed by Verkman and Tamarappoo, the researchers were able to add chemical chaperones, substances that promote the folding of proteins into their proper shape in the ER. The result was that these mutants that would normally be retained in the ER because they were not folded properly were allowed to leave the ER and end up in the apical membrane and AQP2-bearing vesicles. One of these mutants was even able to allow water to pass across the apical membrane, thus showing it had been "functionally rescued" by the chemical chaperones.