Mutations in the vasopressin V2 receptor gene in families with nephrogenic diabetes insipidus and functional expression of the Q-2 mutant

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Item Type:	Article
Title:	Mutations in the vasopressin V2 receptor gene in families with nephrogenic diabetes insipidus and functional expression of the Q-2 mutant
Creators Name:	Rosenthal, W., Seibold, A., Antaramian, A., Gilbert, S., Birnbaumer, M., Bichet, D.G., Arthus, M.F. and Lonergan, M.
Abstract:	Nephrogenic diabetes insipidus (NDI) is characterized by a resistance of the kidney towards arginine vasopressin (AVP). Following molecular cloning of the vasopressin V2 receptor, we identified different mutations in the V2 receptor gene in families with X-linked NDI, which segregated with the disease. The Hopewell mutation (W71X) causes the disease in the largest North American NDI pedigree, with most of its members residing on Nova Scotia. Different mutations were found in three families from the Quebec area (Q-2: R137H, Q-3: R113W, Q-5: 804delG) and in the large Cannon kindred residing in Utah (L312X). In an Iranian family (O-1), another mutation was detected (A132D). Three of the six mutations (Hopewell, Cannon, Q-5) are predicted to cause the expression of a truncated V2 receptor and are therefore unlikely to function. The functional consequences of missense mutations (Q-2, Q-3, O-1) are less obvious. We therefore introduced the Q-2 mutation into wild-type cDNA. When expressed in COS.M6 or Ltk cells, the Q-2 mutant bound AVP with normal affinity. However, cells expressing the Q-2 mutant failed to respond to AVP with an increase in adenylyl cyclase activity. Thus the Q-2 mutant is unable to interact with or to activate the stimulatory G-protein Gs. The present data indicate that X-linked NDI is frequently attributable to a mutation in the V2 receptor gene. In addition, the data prove biochemically that the Q-2 mutation is the cause of NDI in the Q-2 family.
Keywords:	Amino Acid Sequence, DNA Mutational Analysis, Diabetes Insipidus, Gene Frequency, Molecular Sequence Data, Mutation, North America, Point Mutation, Prevalence, Protein Conformation, Vasopressin Receptors, Sequence Deletion, X Chromosome
Source:	Cellular and Molecular Biology
ISSN:	0145-5680
Publisher:	Cellular and Molecular Biology
Volume:	40
Number:	3
Page Range:	429-436
Date:	May 1994
PubMed:	View item in PubMed

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