Endocrine Abstracts

We describe a 3 year old Scottish girl with polyuria and nocturia and a past history of congenital heart disease. In addition to her excess fluid intake she had reduced food intake, failure to thrive and growth failure. Her sister, father, grandfather and a paternal aunt and uncle had a clear history of polyuria, nocturia and excess thirst. A fluid deprivation test revealed peak serum Na, serum and urine osmolalities were 147 mmol/L, 300 mOs/kg, 176 mOs/kg, respectively, in the daughter and 147 mmol/L, 314 mOs/kg, 300 mOs/kg, respectively, in the father. Plasma AVP levels were undetected. Pituitary MRI scan in the father suggested absence of the post pituitary.
Autosomal Dominant Familial Diabetes Insipidus (adFNDI) appears to be largely if not completely penetrant. The genetic locus of adFNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene, which is composed of three exons located on chromosome 20p13. To date, over 40 different heterozygous mutations in the AVP-NPII precursor have been identified in affected families.
After obtaining appropriate consent from involved family members, genomic DNA was extracted from peripheral whole blood. Each of the three exons of the AVP-NPII gene were amplified by PCR and directly sequenced using an automated dye termination method. In the proband and the proband's father, a heterozygous deletion of AGG within base pairs 1824-1829 of exon 2 was found, producing a deletion of glutamine at codon 47 of the neurophysin protein.
Neurophysin is a carrier protein for AVP and is thought to protect AVP from proteolytic degradation. Furthermore, Glu⁴⁷ has been shown to form a salt bridge with AVP. Generation of a mutated neurophysin protein by Glu⁴⁷ deletion could lead to abnormal folding and self-association due to poor affinity of neurophysin for AVP.