Autosomal dominant familial
neurohypophyseal diabetes insipidus (adFNDI) is caused by postnatal
arginine vasopressin (AVP) deficiency resulting from mutations in the AVP gene encoding the AVP pre-prohormone. To advance the understanding of adFNDI further, we have searched for mutations in the AVP gene in 15 unrelated kindreds in which
diabetes insipidus appeared to be segregating. In nine kindreds, seven different previously described mutations were identified. In each of the other six kindreds, unique novel mutations were identified. Two of these (225A>G and 227G>A) change a
nucleotide in the translation
initiation codon of the
signal peptide, whereas the other four (1797T>C, 1884G>A, 1907T>G, and 2112C>G) predict amino-acid substitutions in the
neurophysin II moiety of the AVP prohormone, namely V67A (NP36), G96D (NP65), C104G (NP73), and C116W (NP85). Among these, the mutation predicting the V67A (NP36) substitution is remarkable. It affects a region of the
neurophysin II not affected by any other mutations, produces only a minor change, and its inheritance suggests an incomplete penetrance. Our findings both confirm and further extend the mutation pattern that has emerged in adFNDI, suggesting that the mutations affect
amino-acid residues known or reasonably presumed to be important for the proper folding and/or dimerization of the
neurophysin II moiety of the AVP prohormone.