HETEROGENEOUS AVPR2 GENE-MUTATIONS IN CONGENITAL NEPHROGENIC DIABETES-INSIPIDUS

Mutations in the AVPR2 gene encoding the receptor for arginine vasopre ssin in the kidney (V2 ADHR) have been reported in patients with conge nital nephrogenic diabetes insipidus, a predominantly X-linked disorde r of water homeostasis. We have used restriction-enzyme analysis and d irect DNA sequencing of genomic PCR product to evaluate the AVPR2 gene in 11 unrelated affected males. Each patient has a different DNA sequ ence variation, and only one matches a previously reported mutation. C osegregation 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 fam ily. All the variations predict frameshifts, truncations, or nonconser vative 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 d uplication of the same 28-bp segment, suggesting that both resulted fr om the same unusual unequal crossing-over mechanism facilitated by 9-m er direct sequence repeats. Since the V2 ADHR is a member of the seven -transmembrane-domain, G-protein-coupled receptor superfamily, the los s-of-function mutations from this study and others provide important c lues to the structure-function relationship of this and related recept ors.