IDENTIFICATION OF 13 NEW MUTATIONS IN THE VASOPRESSIN-NEUROPHYSIN-II GENE IN 17 KINDREDS WITH FAMILIAL AUTOSOMAL-DOMINANT NEUROHYPOPHYSEAL DIABETES-INSIPIDUS

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal do minant disorder characterized by progressive postnatal deficiency of a rginine vasopressin as a result of mutation in the gene that encodes t he hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindred s with the disorder. We sequenced all 3 exons of the gene by using a r apid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindre ds each mutation was unique. There were two missense mutations that al tered the cleavage region of the signal peptide, seven missense mutati ons in exon 2, which codes for the conserved portion of the protein, o ne nonsense mutation in exon 2, and three nonsense mutations in exon 3 . These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the producti on of a pre-prohormone that cannot be folded, processed, or degraded p roperly and eventually destroys vasopressinergic neurons.