FAMILIAL NEUROHYPOPHYSEAL DIABETES-INSIPIDUS ASSOCIATED WITH A SIGNALPEPTIDE MUTATION

We studied the pathophysiology, natural history and genetic basis of f amilial neurohypophyseal diabetes insipidus (FNDI) in a caucasian kind red. Twelve members had polyuria and a deficiency of plasma vasopressi n (AVP), which progressed in severity over time. Another had normal ur ine volumes and plasma AVP when first tested at age 3 yr, but develope d severe FNDI a year later. For unknown reasons, one man had a normal urine volume despite severe AVP deficiency and a history of polyuria i n the past. When the AVP-neurophysin-II gene was amplified and sequenc ed, exon 2/3 was normal. but 7 of 12 clones of exon 1 contained a base substitution (G --> A) predicting a substitution of threonine for ala nine at the -1 position of the signal peptide. Restriction analysis fo und the mutation in all 14 affected members, but in none of the 41 con trols or 19 adult members with normal urine volumes and plasma or urin ary AVP (lod score = 5.7). The mutation was also found in 2 infants in whom AVP was normal when tested at 6 and 9 months of age. We hypothes ize that a mutation in exon 1 of the AVP-neurophysin-II gene causes FN DI in this kindred by making an abnormally processed precursor that gr adually destroys vasopressinergic neurons.