A NOVEL POINT MUTATION IN THE TRANSLATION INITIATION CODON OF THE PRE-PRO-VASOPRESSIN-NEUROPHYSIN-II GENE - COSEGREGATION WITH MORPHOLOGICAL ABNORMALITIES AND CLINICAL SYMPTOMS IN AUTOSOMAL-DOMINANT NEUROHYPOPHYSEAL DIABETES-INSIPIDUS

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a ra re variant of idiopathic central diabetes insipidus. Several different mutations in the human vasopressin-neurophysin II (AVP-NP II) gene ha ve been described. We studied nine family members from three generatio ns of an ADNDI pedigree at the clinical, morphological, and molecular levels. AVP concentrations were measured during diagnostic fluid restr iction tests. Coronal and sagittal high resolution T1-weighted images of the pituitary were obtained from affected and healthy family member s. PCR was used to amplify the AVP-NP II precursor gene, and PCR produ cts were directly sequenced. Under maximal osmotic stimulation, AVP se rum levels were close to or below the detection limit in affected indi viduals. Magnetic resonance imaging studies revealed the characteristi c hyperintense (''bright spot'') appearance of the posterior pituitary in two healthy family members. This signal was absent in all four ADN DI patients examined. The coding sequences of AVP and its carrier prot ein, neurophysin II, were normal in all family members examined. Affec ted individuals showed a novel single base deletion (G 227) in the tra nslation initiation codon of the AVP-NP II signal peptide on one allel e. The mutation in the AVP-NP II leader sequence appears to be respons ible for the disease in this kindred, possibly by interfering with pro tein translocation. The absence of the hyperintense posterior pituitar y signal in affected individuals could reflect deficient posterior pit uitary function.