MUTATIONS IN THE VASOPRESSIN V2 RECEPTOR GENE IN 2 FAMILIES WITH NEPHROGENIC DIABETES-INSIPIDUS

Congenital nephrogenic diabetes insipidus (CNDI) is a rare X-linked di sorder in which the renal collecting duct is unresponsive to arginine vasopressin, and thus, the urine is consistently hypotonic to plasma. As a result, affected individuals are unable to concentrate urine and suffer from episodes of severe dehydration and hypernatremia. Recently , the association between arginine vasopressin V2 receptor gene mutati ons and CNDI has been demonstrated. In this report, two additional nov el molecular defects of the arginine vasopressin V2 receptor gene in C NDI families are described. In one family, the affected individual dem onstrated a G --> T transversion causing a nonsense mutation in codon 231. This mutation results in a glutamic acid becoming a termination c odon, causing premature termination and truncation of the encoded rece ptor protein. This mutation causes a Ncil site within the gene to be a bolished and a BsaWI site to be created. in the second family, affecte d individuals showed a 28-basepair duplicating insertion in the very b eginning of exon 2 downstream of the splice acceptor site. It was hypo thesized that an insertion mutagenesis mechanism involves the formatio n of a stem-loop structure within the newly synthesized DNA strand, fo llowed by a slipped mispairing. This may be a general mechanism for th e deletion or insertion of repeated sequences within the genome. Recen t data show that G-protein-coupled receptors are susceptible to many d ifferent mutations that often result in the loss of function, causing a similar clinical phenotype.