Familial neurohypophysial diabetes insipidus in a large Dutch kindred: Effect of the onset of diabetes on growth in children and cell biological defects of the mutant vasopressin prohormone

Familial. neurohypophysial diabetes insipidus (FNDI) is an autosomal domina nt trait in which expression of a mutant vasopressin prohormone reduces vas opressin production. We investigated the NP85 Cys --> Gly mutant vasopressi n prohormone in a large kindred in The Netherlands. We demonstrate that gro wth retardation is an important early sign in two children from this kindre d, which recuperates by substitution therapy with 1-desamino-8-D-arginine v asopressin. To obtain clues about the basis for the dominant inheritance of FNDI, Ne analyzed the trafficking and processing of the mutant vasopressin prohormone in cell lines by metabolic labeling and immunoprecipitation. Th e mutant vasopressin prohormone was retained in the endoplasmic reticulum a nd thus was not processed to vasopressin. This defect was not caused by dim erization of the vasopressin prohormone via its unpaired cysteine residue. High level expression of the mutant vasopressin prohormone in cell lines re sulted in strong accumulation in the endoplasmic reticulum and an altered m orphology of this organelle. We hypothesize that disturbance of the endopla smic reticulum results in dysfunction and ultimately cell death of the cell s expressing the mutant prohormone. Our data support the hypothesis that FN DI is a progressive neurodegenerative disease with delayed onset of symptom s. Its treatment requires early detection of symptoms for which growth para meters are useful.