Molecular Genetic Study of Congenital Nephrogenic Diabetes Insipidus and Rescue of Mutant Vasopressin V2 Receptor by Chemical Chaperones
|Title:||Molecular Genetic Study of Congenital Nephrogenic Diabetes Insipidus and Rescue of Mutant Vasopressin V2 Receptor by Chemical Chaperones|
|Authors:||Cheong, Hae Il; Cho, Hee Yeon; Park, Hye Won; Ha, Il Soo; Choi, Yong|
|Date Published:||April 01, 2007|
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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)
Cheong, et al., studied the vasopressin-2 receptor (V2R) mutations of 14 unrelated Korean boys with Nephrogenic Diabetes Insipidus (NDI). They found 13 different V2R mutations, with eight of these being missense point mutations. In a missense mutation, there is a change in a codon within the gene. This results in a different amino acid than normal being synthesized in the protein that the gene is carrying the code for. So, for example, instead of a leucine amino acid being the 274th protein in the chain of amino acid residues that make up the protein, there is an proline amino acid there instead. The proteins resulting from a missense mutation often have a different shape than the normal protein produced from the gene in question were it were not mutated. These misshapen proteins may be functional, but they are retained in the cell’s quality control system, the endoplasmic reticulum (ER). Instead of being able to travel to their normal job site, these misshapen proteins are held in the ER, then shuttled off to be taken apart.
Of the 13 mutations, the researchers selected 2: A98P and L274P. In addition, they used R113W as a disease control V2R and a normal V2R as control. They incubated the mutant V2Rs in laboratory cell cultures and tested three chemical chaperones - trimethylamine oxide (TMAO), dimethyl sulfoxide (DMSO) and glycerol – to see if they could free the mutant V2Rs from the cell ERs and bring them to the basolateral membrane. This is the part of the membrane the V2R must be in if it is to perform its function.
Treating the laboratory cell cultures with TMAO or DMSO dramatically increased the number of all three mutant V2Rs found in the basolateral membrane, as did incubating the cells at 26 degrees for 6 hours. Treating the cells with glycerol did not help the mutants reach the basolateral membrane. The researchers agree with the hypothesis that the successful chemical chaperones help in the folding process of the synthesizing proteins such that they approximate a more normal shape, in this case the shape a normal V2R is supposed to take.