title: Autosomal dominant neurohypophyseal diabetes insipidus due to substitution of histidine for tyrosine(2) in the vasopressin moiety of the hormone precursor.
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 (T-->C 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.
authors.affiliation: Department of Pediatrics, Skejby University Hospital, DK-8200 Aarhus N, Denmark. rittig@iekf.au.dk
authors.forename: Søren
authors.initials: S
authors.lastname: Rittig
authors.forename: Charlotte
authors.initials: C
authors.lastname: Siggaard
authors.forename: Metin
authors.initials: M
authors.lastname: Ozata
authors.forename: Ilhan
authors.initials: I
authors.lastname: Yetkin
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
authors.forename: Erling B
authors.initials: EB
authors.lastname: Pedersen
authors.forename: Gary L
authors.initials: GL
authors.lastname: Robertson
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D020790:Diabetes Insipidus, Neurogenic / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005799:Genes, Dominant; D006639:Histidine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009481:Neurophysins / Q000235:genetics*; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics*; D014443:Tyrosine; D014667:Vasopressins / Q000235:genetics*
chemical_list: C438657:AVP protein, human; D009481:Neurophysins; D011498:Protein Precursors; D014667:Vasopressins; D014443:Tyrosine; D006639:Histidine