A Novel Mutation in the Arginine Vasopressin Receptor 2 Gene Causing Congenital Nephrogenic Diabetes Insipidus

Abstract

Objective:Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by a renal insensitivity to arginine vasopressin (AVP). In the majority of the cases, CNDI is caused by mutations in the arginine vasopressin receptor 2 (AVPR2) gene. Our objective is to report a novel mutation in the AVPR2 gene causing CNDI in a 6-year-old boy, presenting with growth failure and dull normal cognitive functions.Methods:The proband was the third off-spring of non-consanguineous parents and had polyuria (4.3 L/day), polydipsia (5 L/day). The diagnosis of CNDI was established by a water-deprivation test and a desmopressin challenge test. Genetic studies were also carried out in the mother, siblings and affected family members, since excessive fluid intake and diuresis were also reported in these individuals. All exons of the AVPR2 gene for all participants were amplified and sequenced. Bioinformatics analysis for wild-type and mutant AVPR2 were obtained with Swiss-Model and UCSF Chimera 1.10.2.Results:A novel, hemizygous, missense mutation was identified at the position 80th in exon 2 (p.H80Y) of AVPR2 in the proband. The proband’s mother, maternal aunt and grandmother were heterozygous and his maternal uncle was hemizygous for this mutation. Bioinformatic analysis indicates this mutation would cause significant conformational changes in protein structure.Conclusion:p.H80Y mutation will cause inappropriate folding of the protein compromising water homeostasis via AVPR2 and AVP and leading to diabetes insipidus. We suggest that future functional investigations of the H80Y mutation may provide a basis for understanding the pathophysiology of the NDI in patients with this variant.

[Retracted] A Novel Missense Mutation of Arginine Vasopressin Receptor 2 in a Chinese Family with Congenital Nephrogenic Diabetes Insipidus: X‐Chromosome Inactivation in Female CNDI Patients with Heterozygote 814A>G Mutation

“…Genomic DNA was extracted using a kit (Qiagen, Duesseldorf, Germany). To amplify the AVPR2 and AQP2 genes, polymerase chain reaction (PCR) was performed using primers for AVPR2 and AQP2 genes as previously reported [ 4 , 5 ]. After the purification of PCR products, automated DNA-sequencing was performed using an instrument (310 Genetic Analyzer; ABI Prism) and the BigDye kit (Applied Biosystems, USA).…”

Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

“…Whole exon genomic DNA mutation screening of AVPR2 and AQP2 was performed via Sanger direct sequencing [ 2 , 18 ]. The primers used for PCR are listed in Supplementary Table S1 .…”

“…All target sequences’ exons and flanking intronic regions were amplified by PCR under the following conditions: 60 s at 95 °C, 60 s at 61 °C, and 60 s at 72 °C for 35 cycles. Next, PCR products were separated by electrophoresis in 1.5% agarose gel, purified enzymatically, and sequenced using a Big Dye kit (Applied Biosystems, Beverly, MA, USA) [ 2 ].…”

“…Nephrogenic diabetes insipidus (NDI), congenital or acquired, is characterized by failure to concentrate urine despite stimulated by normal or elevated arginine vasopressin (AVP) levels. Congenital nephrogenic diabetes insipidus (CNDI) is a rare disease with an incidence of 4–8 per 1,000,000 live male births [ 1 , 2 ]. Its onset and associated clinical symptoms are similar regardless of the molecular defect.…”