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Autosomal Dominant Neurohypophyseal Diabetes Insipidus due to Substitution of Histidine for Tyrosine₂ in the Vasopressin Moiety of the Hormone Precursor

Department of Pediatrics (S.R., C.S.) and Research Unit for Molecular Medicine (N.G.), Skejby University Hospital, Aarhus DK-8200, Denmark; Department of Endocrinology (M.O., I.Y.), Gulhane School of Medicine, 06019 Ankara, Turkey; Department of Medicine (E.B.P.), Holstebro Hospital, DK-7500 Holstebro, Denmark; and Department of Medicine (G.L.R.), Northwestern University Medical School, Chicago, Illinois 60611-3008

Address all correspondence and requests for reprints to: Dr. Søren Rittig, M.D., Department of Pediatrics, Skejby University Hospital, DK-8200 Aarhus N, Denmark. E-mail: . rittig{at}iekf.au.dk

Abstract

The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) has been linked to 40 different mutations of the gene encoding the vasopressin-neurophysin II (AVP-NPII) precursor. All of these mutations have been located in either the signal peptide or neurophysin II moiety. We now report a three-generation Turkish kindred in which severe adFNDI cosegregates with a novel missense mutation in the part of the AVP-NPII gene encoding the AVP moiety. This mutation (TC at position 285 in the genomic sequence) was found in only one allele and predicts a substitution of histidine for tyrosine at position 2 in AVP. Like other adFNDI mutations, this substitution is expected to impair folding and processing of the precursor, in this case by interfering with normal binding of the AVP and NPII moieties. It is associated clinically with inability to concentrate urine during fluid deprivation, a greater than 80% deficiency of AVP secretion, and absence of the posterior pituitary bright spot on magnetic resonance imaging. These findings are consistent with the hypothesis that mutations in the AVP-NPII gene cause adFNDI by directing the production of a folding incompetent precursor that prevents the expression of the normal allele via a cytotoxic effect on the magnocellular neurons.

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