Structure and Chromosomal Localization of the Human Antidiuretic Hormone Receptor Gene

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Title: Structure and Chromosomal Localization of the Human Antidiuretic Hormone Receptor Gene
Authors: Seibold, Anita; Brabet, Philippe; Rosenthal, Walter; Birnbaumer, Mariel
Publisher: American Journal of Human Genetics
Date Published: November 01, 1992
Reference Number: 433
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Applying a genomic DNA-expression approach, we cloned the gene and cDNA coding for the human anti-diuretic hormone receptor, also called "vasopressin V2 receptor" (V2R). The nucleotide sequence of both cloned DNAs provided the information to elucidate the structure of the isolated transcriptional unit. The structure of this gene is unusual in that it is the first G protein-coupled receptor gene that contains two very small intervening sequences, the second of which separates the region encoding the seventh transmembrane region from the rest of the open reading frame. The sequence information was used to synthesize appropriate oligonucleotides to be used as primers in the PCR. The V2R gene was localized by PCR using DNA from hybrid cells as template. The gene was found to reside in the q28-qter portion of the human X chromosome, a region identified as the locus for congenital nephrogenic diabetes insipidus.
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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)

When the vasopressin-2 receptor is occupied by the antidiuretic hormone, arginine vasopressin (AVP), adenylyl cyclase is stimulated. This activates cAMP, which stimulates protein kinase A to signal water transporting proteins (called aquaporin-2s) to insert themselves in the membranes of the principal cells of the kidney collecting duct. This makes them more water permeable than usual, allowing the cells to absorb the body water passing through the collecting duct.

In the disorder called congenital nephrogenic diabetes insipidus (NDI) the kidney cannot respond to AVP so it cannot reabsorb water or concentrate urine. This accounts for NDI's primary symptoms: polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst). Researchers tracking the genetic linkage patterns associated with inherited NDI have mapped the position of the gene thought to be responsible for NDI to the q28-qter region of the X chromosome.

Seibold, et al., used genomic DNA extracted from hamster/human hybrid cell lines to localize the V2R gene by using a method called polymerase chain reaction (PCR). PCR amplifies the DNA to produce a sufficient amount for genetic analysis. They then cloned the V2R gene. The authors found the V2R gene had three expressed exons (an exon is a stretch of the gene that contains a coding sequence that instructs the development of the protein the gene synthesizes) and two unusually short introns (stretches of the gene that do not contain coding sequences.)

The first expressed exon is very short, and the second contains the code for approximately 80% of the V2R, up to the beginning of the V2R's seventh transmembrane region. (You can look at a diagram of V2R here.) The third exon codes for the seventh transmembrane region.

Again using PCR analysis, the authors found that the V2R gene was present in the q28-qtr position of the human X chromosome, a region previously identified by another method of analysis, genetic linkage, as the location of the NDI-causing gene. This finding gives strength to the notion that mutant V2R genes are the genes responsible for inherited NDI. The information about the structure and location of the V2R gene should facilitate comparison between the V2R genes of healthy individuals and those of people with NDI.