title: Vasopressin type 2 receptor V88M mutation: molecular basis of partial and complete nephrogenic diabetes insipidus.
abstract: OBJECTIVE
  Mutations in the type 2 vasopressin receptor gene (AVPR2) underlie X-linked recessive nephrogenic diabetes insipidus (NDI). Here, we report on a family with a mutation in AVPR2, c.262G>A (p.V88M). This recurrently identified mutation was previously shown to abolish AVPR2 function, yet in some affected members, urine osmolalities of up to 570 mosm/kg were observed. We detail the variable clinical phenotype and investigate its molecular basis.
  
  
  METHODS
  Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors.
  
  
  RESULTS
  Clinical data were available on 6 patients. Four of these demonstrated a substantial increase in urinary concentration after 1-desamino[8-D-arginine] vasopressin, consistent with partial NDI, while 2 did not respond. In vitro analysis revealed a reduced cell surface expression and decreased binding affinity for arginine-vasopressin of the mutant receptor, leading to blunted signaling activity. Treatment with the pharmacological chaperone SR121463 enhanced cell surface expression.
  
  
  CONCLUSIONS
  The V88M mutation is associated with phenotypical diversity, which may be explained by the fact that both the expression level and the hormone-binding affinity are affected by the mutation. Our results provide a rational basis for treatment trials with vasopressin analogues in combination with pharmacologic chaperones in patients with this recurrently identified mutation.
authors.affiliation: Great Ormond Street Hospital for Children NHS Trust, London, UK. d.bockenhauer@ucl.ac.uk
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Eric
authors.initials: E
authors.lastname: Carpentier
authors.forename: Driss
authors.initials: D
authors.lastname: Rochdi
authors.forename: W
authors.initials: W
authors.lastname: van't Hoff
authors.forename: Billy
authors.initials: B
authors.lastname: Breton
authors.forename: Virginie
authors.initials: V
authors.lastname: Bernier
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D003894:Deamino Arginine Vasopressin; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics* / Q000652:urine; D005260:Female; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000652:urine; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D009318:Natriuresis; D010375:Pedigree; D010641:Phenotype; D011141:Polyuria / Q000209:etiology; D011485:Protein Binding / Q000235:genetics; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012189:Retrospective Studies; D015290:Second Messenger Systems; D013141:Spiro Compounds / Q000494:pharmacology; D014162:Transfection; D014556:Urine / Q000737:chemistry; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: D009025:Morpholines; D017483:Receptors, Vasopressin; D011993:Recombinant Fusion Proteins; D013141:Spiro Compounds; C103281:satavaptan; D000242:Cyclic AMP; D003894:Deamino Arginine Vasopressin