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The Vasopressin Precursor Is Not Processed in the Hypothalamus of Wolfram Syndrome Patients with Diabetes Insipidus: Evidence for the Involvement of PC2 and 7B2

Graduate School Neurosciences, Netherlands Institute for Brain Research (B.A.Th.F.G., D.F.S., D.P.V.D.K., F.W.v.L.), 1105 AZ Amsterdam, The Netherlands; the Department of Neuropathology, Institute of Psychiatry (A.D.), London 3E5 8AF, United Kingdom; the Clinical Research Institute of Montreal (N.G.S.), Montreal H2W1R7, Canada; the Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven Flanders Interuniversity Institute for Biotechnology (J.W.V.d.L., W.J.M.V.d.V.), Leuven 3000, Belgium; and the Department of Animal Physiology, University of Nijmegen (G.W.M.M.), Nijmegen 6525ED, The Netherlands

Address all correspondence and requests for reprints to: Dr. B. A. Th. F. Gabreëls, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, The Netherlands. E-mail: b.gabreels{at}nih.knaw.nl

Wolfram syndrome (WS) is characterized by optic atrophy, insulin-dependent diabetes mellitus, vasopressin (VP)-sensitive diabetes insipidus, and neurosensory hearing loss. Here we report a disturbance in VP precursor processing in the supraoptic and paraventricular nuclei of WS patients. In these patients with diabetes insipidus we could hardly detect any cellular immunoreactivity for processed VP in the supraoptic and paraventricular nuclei. On the other hand, in the paraventricular nucleus a considerable number of cells immunoreactive for the VP precursor were present. In addition, the proprotein convertase PC2 and the molecular chaperone 7B2 were absent. As expression of PC2 and 7B2 was detected in the nearby nucleus basalis of Meynert of one WS patient and in the anterior lobe of the other WS patient, the absence of the two proteins in the paraventricular nucleus was not due to mutations in their genes. These results indicate that in WS patients with diabetes insipidus, not only does VP neuron loss occur in the supraoptic nucleus, but there is also a defect in VP precursor processing.

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