CHARACTERIZATION OF THE MOLECULAR DEFECT IN THE VASOPRESSIN-NEUROPHYSIN II GENE IN A FAMILY WITH AUTOSOMAL DOMINANT NEUROHYPOPHYSEAL DIABETES INSIPIDUS

Abstract

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a rare familial form of vasopressin-deficient DI. In previous studies, we have shown genetic linkage between ADNDI and the argmine vasopressin-neurophysin II (AVP-NP II) gene locus. This gene contains 3 exons that encode AVP, its carrier protein NP II, and a small glycoprotein. We obtained genomic DNA from a 25 yr old woman with longstanding DI, her 2 year old affected daughter, and her husband and unaffected daughter. Each of the three exons of the AVP-NP II genes of these individuals was amplified by polymerase chain reaction and sequenced by thermocycle sequencing. In the affected individuals, a single nucleotide mutation (C → T) was detected in exon II of the AVP-NP II gene. The nucleotide sequence of exons I and III were completely normal. These affected individuals also have one normal allele of the AVP-NP II gene. The mutation encodes a Pro → Leu substitution in the NP II protein. This mutation also destroys an Apa I restriction enzyme recognition site and creates a Dde I site. To ensure that this mutation is not a common, genetically silent polymorphism in the sequence of the AVP-NP II gene, we amplified exon II of 50 control individuals representing 100 AVP-NP II genes to screen for the presence of this nucleotide change. Neither absence of the Apa I restriction site nor presence of the Dde 1 site was detected in control individuals, suggesting that this mutation is the cause of ADNDI in the affected family. The mechanism by which vasopressin deficiency results from a mutation in one of a person's two NP II-encoding sequences is under investigation.