title: Two novel mutations in the coding region for neurophysin-II associated with familial central diabetes insipidus.
abstract: Familial central diabetes insipidus is an autosomal dominant disease caused by a deficiency of arginine vasopressin (AVP). We previously reported three distinct mutations in the AVP gene in Japanese familial central diabetes insipidus pedigrees that result in a substitution of Ser for Gly57 in the neurophysin-II (NPII) moiety of the AVP precursor, a substitution of Thr for Ala at the COOH-terminus of the signal peptide, and a deletion of Glu47 in the NPII moiety. In this study, we analyzed the AVP gene in two pedigrees by direct sequencing of the polymerase chain reaction-amplified DNA and found two novel mutations in exon 2, which encodes the central part of the NPII moiety of the precursor. The mutation in one pedigree was a C to A transition at nucleotide position 1891, which replaces Cys67 (TGC) with stop codon (TGA). As the premature termination eliminates part of the COOH domain of the NPII moiety and the glycoprotein moiety, the conformation of the truncated protein is likely to be markedly different from that of normal precursor. In another pedigree, a G to T transversion was detected at nucleotide position 1874, which substitutes polar Trp (TGG) for hydrophobic Gly62 (GGG). It is possible that mutated NPII molecules, as a consequence of a conformational change, cannot bind AVP or self-associate to form higher oligomer complexes. Interestingly, all mutations we have identified to date, with the exception of the signal peptide mutation, are located in exon 2, suggesting the importance of the highly conserved central part of the NPII molecules and/or the NPII moiety in the precursor for AVP synthesis.
authors.affiliation: First Department of Internal Medicine, Nagoya University School of Medicine, Aichi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nagasaki
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Yuasa
authors.forename: H
authors.initials: H
authors.lastname: Saito
authors.forename: M
authors.initials: M
authors.lastname: Fukase
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.forename: E
authors.initials: E
authors.lastname: Ishikawa
authors.forename: H
authors.initials: H
authors.lastname: Katakami
authors.forename: Y
authors.initials: Y
authors.lastname: Oiso
mesh_terms: D000293:Adolescent; D000328:Adult; D001127:Arginine Vasopressin / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D003919:Diabetes Insipidus / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009481:Neurophysins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: D015335:Molecular Probes; D009481:Neurophysins; D001127:Arginine Vasopressin; D004247:DNA