IDENTIFICATION OF A NOVEL NONSENSE MUTATION AND A MISSENSE SUBSTITUTION IN THE VASOPRESSIN-NEUROPHYSIN-II GENE IN 2 SPANISH KINDREDS WITH FAMILIAL NEUROHYPOPHYSEAL DIABETES-INSIPIDUS

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal do minant disease caused by deficiency in the antidiuretic hormone argini ne vasopressin (AVP) encoded by the AVP-neurophysin II (AVP-NPII) gene on chromosome 20p13. In this study, we analyzed two families with FND I using direct automated fluorescent, solid phase, single-stranded DNA sequencing of PCR-amplified AVP-NPII DNA. In one of the families, aff ected individuals presented a novel nonsense mutation in exon 3 of the gene, consisting in a G to T transition at nucleotide 2101, which pro duces a stop signal in codon 82 (Glu) Of NPII. The premature terminati on eliminates part of the C-terminal domain of NPII, including a cyste ine residue in position 85, which could be involved in the correct fol ding of the prohormone. In the second family, a G279A substitution at position -1 of the signal peptide was observed in all affected individ uals. This missense mutation, which replaces Ala with Thr, is frequent among FNDI patients and is thought to reduce the efficiency of cleava ge by signal peptidases.