Abstract
Congenital nephrogenic diabetes insipidus (CNDI) is characterized by the reduced ability of renal collecting duct cells to reabsorb water in response to the antidiuretic effect of vasopressin. Chronic polyuria and polydipsia are the hallmarks of the disease. Approximately 90% of all patients with CNDI have X-linked inherited disease caused by variants in the arginine vasopressin receptor 2 (AVPR2) gene. We present genetic findings in 34 individuals from 19 kindreds including one or more family members with CNDI. Coding regions of AVPR2 were sequenced bi-directionally. We identified eight novel disease-causing variants in AVPR2, p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro in nine kindreds. In all three families with more than one affected individual, the novel variants segregated with the disease. We also identified eight recurrent disease-causing variants, p.Val88Met, p.Leu111Valfs*80, p.Arg113Trp, p.Tyr124*, p.Ser167Leu, p.Thr207Asn, p.Arg247Alafs*12, and p.Arg337* in ten kindreds. Our findings contribute to the growing list of AVPR2 variants causing X-linked CNDI.
Conclusion: Being a rapid diagnostic tool for CNDI, direct sequencing of AVPR2 should be encouraged in newborns with familial predisposition to CNDI.
What is Known: • Disease-causing variants in AVPR2 cause X-linked congenital nephrogenic diabetes insipidus (CNDI). • DNA sequencing of AVPR2 is rapid, facilitates differential diagnosis, early intervention, and genetic diagnosis thus reducing morbidity in CNDI. |
What is New: • We identified eight novel disease-causing variants in AVPR2: p.Arg68Alafs*124, p.Ser171Arg, p.Gln174Pro, p.Trp200Arg, p.Gly201Cys, p.Gly220Arg, p.Val226Glu, and p.Gln291Pro, thereby adding to the growing list of AVPR2 disease-causing variants and emphasizing the importance of genetic testing in CNDI. |
Abbreviations
- AQP2:
-
Aquaporin 2
- AVP:
-
Arginine-vasopressin
- AVPR2:
-
Arginine-vasopressin receptor 2
- CNDI:
-
Congenital nephrogenic diabetes insipidus
- NMD:
-
Nonsense-mediated decay
- TMD:
-
Transmembrane domain
- V2R:
-
V2 receptor or arginine-vasopressin receptor 2
References
Abrol R, Kim SK, Bray JK, Griffith AR, Goddard WA III (2011) Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins. Methods 55(4):405–414. https://doi.org/10.1016/j.ymeth.2011.12.005
Bichet DG, Bockenhauer D (2016) Genetic forms of nephrogenic diabetes insipidus (NDI): vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant). Best Pract Res Clin Endocrinol Metab 30(2):263–276. https://doi.org/10.1016/j.beem.2016.02.010
Bichet DG, Arthus MF, Lonergan M, Hendy GN, Paradis AJ, Fujiwara TM, Morgan K, Gregory MC, Rosenthal W, Didwania A et al (1993) X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. J Clin Invest 92(3):1262–1268. https://doi.org/10.1172/JCI116698
Bichet DG, Birnbaumer M, Lonergan M, Arthus MF, Rosenthal W, Goodyer P, Nivet H, Benoit S, Giampietro P, Simonetti S et al (1994) Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet 55(2):278–286
Boselt I, Tramma D, Kalamitsou S, Niemeyer T, Nykanen P, Graf KJ, Krude H, Marenzi KS, Di Candia S, Schoneberg T, Schulz A (2012) Functional characterization of novel loss-of-function mutations in the vasopressin type 2 receptor gene causing nephrogenic diabetes insipidus. Nephrol Dial Transplant 27(4):1521–1528. https://doi.org/10.1093/ndt/gfr487
Cheong HI, Park HW, Ha IS, Moon HN, Choi Y, Ko KW, Jun JK (1997) Six novel mutations in the vasopressin V2 receptor gene causing nephrogenic diabetes insipidus. Nephron 75(4):431–437
Faerch M, Christensen JH, Corydon TJ, Kamperis K, de Zegher F, Gregersen N, Robertson GL, Rittig S (2008) Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene. Clin Endocrinol 68(3):395–403. https://doi.org/10.1111/j.1365-2265.2007.03054.x
Faerch M, Christensen JH, Rittig S, Johansson JO, Gregersen N, de Zegher F, Corydon TJ (2009) Diverse vasopressin V2 receptor functionality underlying partial congenital nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 297(6):F1518–F1525. https://doi.org/10.1152/ajprenal.00331.2009
Faerch M, Corydon TJ, Rittig S, Christensen JH, Hertz JM, Jendle J (2010) Skewed X-chromosome inactivation causing diagnostic misinterpretation in congenital nephrogenic diabetes insipidus. Scand J Urol Nephrol 44(5):324–330. https://doi.org/10.3109/00365599.2010.482946
Fujiwara TM, Bichet DG (2005) Molecular biology of hereditary diabetes insipidus. J Am Soc Nephrol 16(10):2836–2846. https://doi.org/10.1681/ASN.2005040371
Lehner B (2007) Modelling genotype-phenotype relationships and human disease with genetic interaction networks. J Exp Biol 210(Pt 9):1559–1566. https://doi.org/10.1242/jeb.002311
Robben JH, Knoers NV, Deen PM (2006) Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 291(2):F257–F270. https://doi.org/10.1152/ajprenal.00491.2005
Sadeghi H, Robertson GL, Bichet DG, Innamorati G, Birnbaumer M (1997) Biochemical basis of partial nephrogenic diabetes insipidus phenotypes. Mol Endocrinol 11(12):1806–1813. https://doi.org/10.1210/mend.11.12.0017
Spanakis E, Milord E, Gragnoli C (2008) AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. J Cell Physiol 217(3):605–617. https://doi.org/10.1002/jcp.21552
Wildin RS, Antush MJ, Bennett RL, Schoof JM, Scott CR (1994) Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus. Am J Hum Genet 55(2):266–277
Acknowledgements
We would like to thank the patients and their family members for their cooperation. Jane Knudsen, Margrethe Kjeldsen, and Hong Bich Thi Pham are thanked for their technical assistance. We sincerely thank Dr. Gary L. Robertson, Dr. Lene Rytter, Dr. Ekaterini Siomou, Dr. Hans-Henrik Levang, Dr. Hanne Nørgaard, Dr. Elsebet Østergaard, Dr. Kirsten Rasmussen, Dr. Price, Dr. Clayton, Dr. Kay Metcalfe, late Dr. Nana Thrane, Dr. Hamideh Rastkhani, Dr. Kathrina Main, Dr. Sten A. Ivarsson, Dr. Niels Foged, Dr. Joerg Seidel, Dr. Dina Cortes, Dr. Karsten Hjelt, and late Dr. Laszlo Kovacs for clinical referrals of patients included in this article.
Funding
Familien Hede Nielsens Fond, Denmark, funded the DNA sequence analysis software.
Author information
Authors and Affiliations
Contributions
Shivani Joshi—drafting the article and revising it critically for important intellectual content.
Shivani Joshi, Helene Kvistgaard, Konstantinos Kamperis, Mia Færch, Søren Hagstrøm, Niels Gregersen, Søren Rittig, Jane Hvarregaard Christensen—substantial contributions to conception and design, acquisition of data, data analysis and interpretation as well as editing the manuscript.
Jane Hvarregaard Christensen—final approval of the version to be submitted and any revised version.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Informed consent
For this type of study, formal consent is not required. Additionally, the Regional Committee on Biomedical Research Ethics Denmark agreed that ethical approval and consent to participate was not required for the current study, as patients were referred for clinical diagnostic testing by the clinicians.
Additional information
Communicated by Mario Bianchetti
Rights and permissions
About this article
Cite this article
Joshi, S., Kvistgaard, H., Kamperis, K. et al. Novel and recurrent variants in AVPR2 in 19 families with X-linked congenital nephrogenic diabetes insipidus. Eur J Pediatr 177, 1399–1405 (2018). https://doi.org/10.1007/s00431-018-3132-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-018-3132-z