2 NOVEL MUTATIONS OF THE VASOPRESSIN GENE ASSOCIATED WITH FAMILIAL DIABETES-INSIPIDUS AND IDENTIFICATION OF AN ASYMPTOMATIC CARRIER INFANT

Familial diabetes insipidus (FDI) is a syndrome of central vasopressin deficiency that is inherited in an autosomal dominant manner and that typically becomes clinically apparent in the first decade of life. Tw o novel mutations of the vasopressin gene have been identified in two previously unstudied kindreds with FDI. In each kindred, the inheritan ce of the FDI phenotype was consistent with an autosomal dominant mode of inheritance. In each proband, the diagnosis of central diabetes in sipidus had been confirmed previously with a water deprivation protoco l. After extraction of genomic DNA from each individual, the three exo ns of the vasopressin gene were separately amplified by PCR and direct ly sequenced using an automated dye termination method. In the proband and two other carriers of one kindred, a heterozygous C to T mutation was identified at nucleotide 1857. This is predicted to produce a ser ine to phenylalanine substitution at residue 56 of the vasopressin-rel ated neurophysin peptide encoded by the mutated allele. The mutation a lso abolished an MspI site in the vasopressin sequence, and analysis o f genomic DNA from eight members of the kindred (five with FDI) confir med segregation of the mutation with the FDI phenotype. Another member of the kindred, a 13-month-old infant, also has the heterozygous C to T mutation, but a formal water balance study showed no evidence of di abetes insipidus. In the proband of the other kindred, a heterozygous G to A mutation was identified at nucleotide 1873. This mutation would be predicted to cause a cysteine to tyrosine substitution at residue 61 of the neurophysin encoded by the mutated allele. This heterozygous mutation was confirmed by the presence of an RsaI restriction site in one vasopressin allele in two members of the kindred. Therefore, two novel heterozygous mutations of the vasopressin gene have been identif ied in FDI kindreds. In one kindred, an asymptomatic carrier infant wa s identified and will require continued observation to determine wheth er she will develop clinical diabetes insipidus. The presence of these two novel mutations in a region of the vasopressin gene where other F DI mutations have been reported suggests that the part of the neurophy sin peptide encoded by these sequences may be critically important in the appropriate expression of vasopressin.