Heterogeneous AVPR2 Gene Mutations in Congenital Nephrogenic Diabetes Insipidus

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Title: Heterogeneous AVPR2 Gene Mutations in Congenital Nephrogenic Diabetes Insipidus
Authors: Wildin, Robert; Antush, Mark J.; Bennett, Robin L.; Schoof, Jonathan M.; Scott, C. Ronald
Publisher: American Journal of Human Genetics
Date Published: August 01, 1994
Reference Number: 93
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Mutations in the AVPR2 gene encoding the receptor for arginine vasopressin in the kidney (V2 ADHR) have been reported in patients with congenital nephrogenic diabetes insipidus, a predominantly X-linked disorder of water homeostasis. We have used restriction-enzyme analysis and direct DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequence variation, and only one matches a previously reported mutation. Cosegregation of the variations with nephrogenic diabetes insipidus was demonstrated for two families, and a de novo mutation was documented in two additional cases. Carrier detection was accomplished in one family. All the variations predict frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions in the V2 ADHR and related receptors. Of interest, a 28-bp deletion is found in one patient, while another, unrelated patient has a tandem duplication of the same 28-bp segment, suggesting that both resulted from the same unusual unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats. Since the V2 ADHR is a member of the seven-transmembrane-domain, G-protein-coupled receptor superfamily, the loss-of-function mutations from this study and others provide important clues to the structure-function relationship of this and related receptors.
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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)

Nephrogenic diabetes insipidus (NDI) is a disorder characterized by the kidney's inability to respond to the antidiuretic hormone, arginine vasopressin (AVP). As a result, the kidney is not able to concentrate urine or maintain body water balance. NDI may be either acquired or inherited. The most common form of inherited NDI is X-linked recessive NDI where a mutated arginine vasopressin 2 receptor (AVPR2) gene is carried and transmitted on the X chromosome. Mutated AVPR2 genes can produce defective arginine vasopressin-2 receptors (AVPR2s). These defective receptors fail in their function of binding with AVP and initiating the molecular sequence that allows the kidneys to concentrate urine and maintain body water balance. As an X-linked recessive disorder, it is carried by females who generally do not show any symptoms of NDI. Female carriers can transmit the mutated AVPR2 gene to either their male or female offspring, but it is the male who will express the symptoms of NDI. The symptoms include chronic, excessive urination (polyuria) and chronic, excessive thirst (polydipsia).

Wildin, et al., analyzed 11 unrelated families in which a mutation in the AVPR2 gene was associated with NDI. The authors' analysis revealed that each of the 11 NDI patients (there was one patient in each family) had a unique AVPR2 mutation, only one of which had been previously reported in the literature.

The AVPR2 gene is responsible for manufacturing the AVPR2, which, like all products of genes, is a protein. Each gene is formed by a combination of four nucleotide bases: adenine (A), cytosine (C), guanine (G), and thymine (T). The combination differs for each gene. For example, a part of one gene's base sequence might look like this: TGCTCCTCAGGCAGG. Cells have a decoding apparatus that reads the base sequences three at a time (e.g. TGC). Each unit of three bases is called a codon, and each codon codes for a single amino acid (the building blocks of protein). So if a mutation in a gene disrupts a codon, that codon could produce a different amino acid, which in turn would go into the amino acid mix that builds the protein. The changed amino acid would effect the final structure of the protein (in this case, the AVPR2). An altered protein structure like an altered AVPR2 could affect its ability to function properly or at all.

Scientists believe the AVPR2 sits within the membranes of the principal cells of the kidney collecting duct. The cell membrane is a thin band of tissue that encircles a cell, separating the outside of the cell from the inside. If you imagine the AVPR2 as a beaded string, the majority of it lies folded in seven clumps within the membrane. These clumps are called transmembrane regions and are numbered 1 through 7. Part of the AVPR2 snakes outside the cell membrane, forming extracellular loops 1, 2 and 3. Part of it snakes inside the cell, forming intracellular loops 1, 2 and 3. One end of the AVPR2, called the amino-terminus, sits outside the cell with the extracellular loops. The other end, called the carboxy-terminus, sits inside the cell with the intracellular loops. (Look at a diagram of a vasopressin-2 receptor gene).

The authors made several generalizations about the AVPR2 based on the nature of the mutations of their subjects' AVPR2 genes:
  1. The frameshift mutations (which produce a different set of amino acids than normal to make the AVPR2) and nonsense mutations (which cause the gene to prematurely end its protein manufacture) would disrupt one or more of the receptor's seven transmembrane regions.
  2. The point mutations (which is a change in a single base pair in the gene, e.g. a C-to-T or a G-to-A transition and results in amino acid substitutions) cluster in or near the seven transmembrane regions.
  3. Other receptors closely related to the AVPR2 have substitution mutations (where a single base is substituted for the expected base) occurring at similar positions as the substitute mutations on the AVPR2.
  4. No single region of the AVPR2's primary amino acid sequence has a significant clustering of mutations.
These observations emphasize the functional importance of the structure of the AVPR2's transmembrane regions and suggest that all the segments of the receptor contribute to the formation of a functional AVPR2.

Four of the authors' NDI patients had no family history of inherited NDI. The authors analyzed the AVPR2 gene of two mothers out of these four patients and found that though their AVPR2 genes were normal, their sons' AVPR2 genes were mutated. This provides direct evidence that AVPR2 mutation can cause congenital NDI.