A missense mutation encoding Cys73Phe in neurophysin II is associated with autosomal dominant neurohypophyseal diabetes insipidus

• Published in: Molecular genetics and metabolism 2002-09, Vol.77 (1), p.112-118
• Main Authors: Santiprabhob, Jeerunda, Browning, James E, Repaske, David R
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Amino Acid Sequence; Amino Acid Substitution; Arginine vasopressin; Autosomal dominant neurohypophyseal diabetes insipidus; Base Sequence; Diabetes insipidus; Diabetes Insipidus, Neurogenic - genetics; DNA - genetics; DNA Mutational Analysis; Female; Genes, Dominant; Heterozygote; Humans; Infant; Male; Mutation; Mutation, Missense; Neurophysin II; Neurophysins - chemistry; Neurophysins - genetics; Pedigree; Polymerase Chain Reaction; Protein Precursors - chemistry; Protein Precursors - genetics
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/S1096-7192(02)00118-X

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is an inherited disease caused by progressive deficiency of the hormone arginine vasopressin (AVP) that typically becomes clinically apparent in the first decade of life. The genetic locus of ADNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene and mutations that cause ADNDI have been found in the nucleotides encoding the signal peptide, vasopressin, and neurophysin II peptides. In this study we have analyzed the AVP-NPII gene in a 20-year-old female who was diagnosed with ADNDI at 2 years of age. A heterozygous missense mutation (1684G>T) was found in exon 2 that predicts replacement of cysteine with phenylalanine at position 73 of neurophysin II. The mutation was confirmed by subcloning exon 2 PCR products to sequence each allele independently. Two out of four clones were found to have the missense mutation and two have the normal sequence, confirming the presence of the mutation and heterozygosity. Neurophysin II is an intracellular carrier protein for AVP during axonal transport from the hypothalamus to the posterior pituitary and contains 14 cysteine residues forming 7 disulfide bonds. This mutation is predicted to disrupt the disulfide bridge between Cys73 and Cys61 within the neurophysin II moiety. This finding of a novel mutation substituting cysteine with phenylalanine in one AVP-NPII gene allele supports the hypothesis that inability to form normal disulfide bonds in neurophysin II leads to ADNDI.