Vasopressin type 2 receptor V88M mutation: molecular basis of partial and complete nephrogenic diabetes insipidus.
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.
Bockenhauer
Detlef
D
Great Ormond Street Hospital for Children NHS Trust, London, UK. d.bockenhauer@ucl.ac.uk
Carpentier
Eric
E
Rochdi
Driss
D
van't Hoff
W
W
Breton
Billy
B
Bernier
Virginie
V
Bouvier
Michel
M
Bichet
Daniel G
DG
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
D009025:Morpholines; D017483:Receptors, Vasopressin; D011993:Recombinant Fusion Proteins; D013141:Spiro Compounds; C103281:satavaptan; D000242:Cyclic AMP; D003894:Deamino Arginine Vasopressin