Autosomal dominant neurohypophyseal diabetes insipidus in a Swiss family, caused by a novel mutation (C59 Delta/A60W) in the neurophysin moiety of prepro-vasopressin-neurophysin II (AVP-NP II)

Objective: To study clinical, morphological and molecular characteristics i n a Swiss family with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). Participants and methods: A 15-month-old girl presenting with symptoms of p olydipsia and polyuria was investigated by water deprivation test. Evaluati on of the family revealed three further family members with symptomatic vas opressin-deficient diabetes insipidus. T1-weighted magnetic resonance image s of the posterior pituitary were taken in two affected adult family member s and molecular genetic analysis was performed in all affected individuals. Results: The water deprivation test in the 15-month-old child confirmed the diagnosis of vasopressin-deficient diabetes insipidus and the pedigree was consistent with autosomal dominant inheritance. The characteristic bright spot of the normal vasopressin-containing neurophypophysis was absent in bo th adults with adFND1. Direct sequence analysis revealed a new deletion (17 7-179 Delta CGC) in exon 2 of the AVP-NP II gene in all affected individual s. At the amino acid level, this deletion eliminates cysteine 59 (C59 Delta ) and substitutes alanine 60 by tryptophan (A60W) in the AVP-NP II precurso r: interestingly, the remainder of the reading frame remains unchanged. Acc ording to the three-dimensional structure of neurophysin, C59 is involved i n a disulphide bond with C65. Conclusions: Deletion of C59 and substitution of A60W in the AVP-NP II prec ursor is predicted to disrupt one of the seven disulphide bridges required for correct folding of the neurophysin moiety and thus disturb the function of neurophysin as the vasopressin transport protein. These data are in lin e with the clinical and morphological findings in the reported family with adFND1.