Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene

Objective To identify the molecular basis and clinical characteristics of X-linked congenital nephrogenic diabetes insipidus (CNDI) presenting with an unusual phenotype characterized by partial resistance to AVP. Subjects The proband was admitted at the age of 4 years with a history of polydipsia and polyuria since infancy. Initial clinical testing confirmed a diagnosis of diabetes insipidus (DI). Urine osmolarity rose during fluid deprivation and after 20 mu g of intranasal desmopressin [1-deamino-8-D-arginine-vasopressin (dDAVP)]. A similar DI phenotype was found in his brother. Methods The coding regions of the AVP gene and the AVP receptor 2 (AVPR2) genes were sequenced in two affected and three unaffected family members. Clinical studies included a fluid deprivation test, intranasal dDAVP challenge, infusion of graded doses of dDAVP and AVP, and measurements of 24-h urine output before and at the end of a 7-day therapeutic trial of intranasal dDAVP. Results A novel missense mutation (1454C > A) in exon 3 of the AVPR2 gene predicting a Ser329Arg substitution was identified in the X-chromosome of the two affected brothers and in one of the X-chromosomes in the mother. The AVPR2 gene was normal in two unaffected siblings. Under basal conditions, the 24-h urine volumes of the two affected boys were 5.5 l (229 ml/kg) and 3.5 l (192 ml/kg), the urine osmolalities were 78 and 90 mosm/kg, and plasma AVP 13.5 and 19.0 pg/ml. Urine osmolalities increased to 573 and 720 mosm/kg while plasma AVP levels were practically unchanged, 13.6 and 8.8 pg/ml, during fluid deprivation. Infusion of AVP resulted in urine osmolalities of 523 and 623 mosm/kg at plasma AVP levels of 58 and 42 pg/ml. Infusion of dDAVP had a similar effect, while treatment with standard doses of intranasal dDAVP had no effect on urine output. Discussion The affected members of this Belgian kindred have CNDI with partial resistance to AVP caused by a mutation in the AVPR2 gene that differs from any of the six mutations reported previously to produce this phenotype. Because the resistance to AVP is partial, this form of CNDI can be difficult to distinguish by indirect diagnostic tests from partial pituitary and dipsogenic DI.