A missense mutation in the vasopressin-neurophysin precursor gene cosegregates with human autosomal dominant neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus in humans is a rare disease transmitted as an autosomal dominant trait. Affected individuals have very low or undetectable levels of circulating vasopressin and suffer from polydipsia and polyuria. An obvious candidate gene for the disease is the vasopressin-neurophysin (AVP-NP) precursor gene on human chromosome 20. The 2 kb gene with three exons encodes a composite precursor protein consisting of the neuropeptide vasopressin and two associated proteins, neurophysin and a glycopeptide. Cloning and nucleotide sequence analysis of both alleles of the AVP-NP gene present in a Dutch ADNDI family reveals a point mutation in one allele of the affected family members. Comparison of the nucleotide sequences shows a G----T transversion within the neurophysin-encoding exon B. This missense mutation converts a highly conserved glycine (Gly17 of neurophysin) to a valine residue. RFLP analysis of six related family members indicates cosegregation of the mutant allele with the DI phenotype. The mutation is not present in 96 chromosomes of an unrelated control group. These data suggest that a single amino acid exchange within a highly conserved domain of the human vasopressin-associated neurophysin is the primary cause of one form of ADNDI.

Expression of the vasopressin and oxytocin genes in rats occurs in mutually exclusive sets of hypothalamic neurons.

The genes for the hypothalamic hormones vasopressin and oxytocin are located in close proximity to each other within the rat genome. They are separated by only approx. 11 kbp of DNA sequence and oriented in such a way that their transcription occurs on opposite DNA strands. Although the two genes are structurally very similar including common potential regulatory elements in their putative promotor regions, they are expressed in discrete populations of magnocellular neurons of the hypothalamus. In rats placed under osmotic stress, the vasopressin gene is upregulated; concomitantly transcription of the oxytocin gene is also stimulated. To address the question of whether this coordinated rise in oxytocin-encoding mRNA is the result of switching on oxytocin gene transcription in vasopressinergic neurons, in situ hybridization with double labelled cRNA probes was carried out. Biotinylated and [alpha-35S]CTP labelled antisense cRNA probes specific for either vasopressin or oxytocin mRNA were constructed and hybridized to hypothalamic sections from salt-loaded rats. The results demonstrate that upregulation of oxytocin gene transcription is restricted solely to oxytocinergic cells; no oxytocin gene transcripts can be detected in vasopressinergic neurons.