A NOVEL MUTATION IN THE CODING REGION FOR NEUROPHYSIN-II IS ASSOCIATED WITH AUTOSOMAL-DOMINANT NEUROHYPOPHYSEAL DIABETES-INSIPIDUS

OBJECTIVE Autosomal dominant neurohypophyseal diabetes insipidus (ADND I) is a rare cause of diabetes insipidus, in which AVP serum levels ar e insufficient. AVP is synthesized along with neurophysin-II (NPII) as an AVP-NPII precursor polypeptide in the hypothalamus. After proteoly tic cleavage during axonal transport, AVP and NPII are reassembled and stored loosely bound to each other in the posterior pituitary until b oth are released into the circulation. In this study, we investigated the genetic basis of ADNDI in a German kindred with 10 affected member s spanning three generations. DESIGN Genomic DNA was isolated from per ipheral blood leucocytes. The entire coding region of the AVP-NPII gen e of one of the affected persons was amplified by polymerase chain rea ction (PCR) and subjected to nucleotide sequence analysis. Sequencing results were confirmed by restriction enzyme analysis of PCR products. PATIENTS Six affected and two unaffected members of a family with ADN DI and 54 unrelated healthy control subjects were studied. RESULTS The index patient was found by direct sequencing to be heterozygous for a G to T transversion at nucleotide position 1884 (exon 2) of the AVP-N PII gene, This mutation introduced a new recognition site for the rest riction enzyme Ava II, which was used to test for the presence of the mutation in other family members and in control subjects. The mutation was detected in all family members with ADNDI, but was not found in u naffected family members or In control subjects. The mutation encodes a valine in place of the normal glycine at amino acid 65 of NPII, whic h is known to be highly conserved during evolution. CONCLUSIONS In thi s family, the autosomal dominant neurohypophyseal diabetes insipidus p henotype cosegregates with a point mutation in a region of the AVP-neu rophysin-II gene which codes for the carboxyterminal domain of neuroph ysin-II. Although the altered amino acid is not directly involved in A VP binding, the mutation might lead to conformational changes that imp air the dimerization of neurophysin-II molecules. this could in turn a ffect the AVP binding affinity of neurophysin-II or might interfere wi th the transport of the AVP-neurophysin-II precursor in the AVP-produc ing cells of the hypothalamus.