2 NOVEL MUTATIONS IN THE CODING REGION FOR NEUROPHYSIN-II ASSOCIATED WITH FAMILIAL CENTRAL DIABETES-INSIPIDUS

Familial central diabetes insipidus is an autosomal dominant disease c aused by a deficiency of arginine vasopressin (AVP). We previously rep orted three distinct mutations in the AVP gene in Japanese familial ce ntral diabetes insipidus pedigrees that result in a substitution of Se r for Gly(57) in the neurophysin-II (NPII) moiety of the AVP precursor , a substitution of Thr for Ala at the COOH-terminus of the signal pep tide, and a deletion of Glu(47) in the NPII moiety. In this study, we analyzed the AVP gene in two pedigrees by direct sequencing of the pol ymerase chain reaction-amplified DNA and found two novel mutations in exon 2, which encodes the central part of the NPII moiety of the precu rsor. The mutation in one pedigree was a C to A transition at nucleoti de position 1891, which replaces Cys(67) (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 trun cated protein is likely to be markedly different from that of normal p recursor. In another pedigree, a G to T transversion was detected at n ucleotide position 1874, which substitutes polar Trp (TGG) for hydroph obic Gly(62) (GGG). It is possible that mutated NPII molecules, as a c onsequence of a conformational change, cannot bind AVP or self-associa te to form higher oligomer complexes. Interestingly, all mutations we have identified to date, with the exception of the signal peptide muta tion, are located in exon 2, suggesting the importance of the highly c onserved central part of the NPII molecules and/or the NPII moiety in the precursor for AVP synthesis.