Journal of Endocrinological Investigation

, Volume 27, Issue 2, pp 167–170 | Cite as

A novel deletion mutation in the arginine vasopressin receptor 2 gene and skewed X chromosome inactivation in a female patient with congenital nephrogenic diabetes insipidus

  • K. Kinoshita
  • Y. Miura
  • H. Nagasaki
  • T. Murase
  • Y. Bando
  • Y. Oiso
Case Report


X-linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder caused by mutations in the arginine vasopressin receptor 2 (V2R) gene. The clinical phenotype is fully expressed in hemizygous male patients and is usually asymptomatic in heterozygous females. In the present study, a 51-yr-old Japanese female with congenital NDI and her family members were examined. The patient developed severe hypernatremia accompanied by hypoosmotic polyuria after gynecological surgery, and was unable to concentrate urinary osmolality in response to exogenous vasopressin. Direct sequencing analysis of the propositus and her two affected sons revealed a two-nucleotide deletion change at codon 30 (g.452–453delAC) in the V2R gene, resulting in a frameshift and premature termination in translation at codon 190. The X chromosome inactivation pattern was investigated in the propositus using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene, and the value for relative X chromosome inactivation of one allele was 70.2%. In conclusion, we identified a novel V2R gene mutation in a female patient and her sons with congenital NDI, and her phenotype may be caused by skewed X chromosome inactivation.


nephrogenic diabetes insipidus ADH X chromosome inactivation polyuria androgen receptor 


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  1. 1.
    Deen PMT, Verdijk MAJ, Knoers NVAM, et al. Requirement of human renal water channel aquaporin-2 for vasopressindependent concentration of urine. Science 1994, 264: 92–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Lieburg AF, Verdijk MAJ, Knoers VVAM, et al. Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. Am J Hum Genet 1994, 55: 648–52.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Birnbaumer M, Seibold A, Gilbert S, et al. Molecular cloning of the receptor for human antidiuretic hormone. Nature 1992, 357: 333–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Seibold A, Brabet P, Rosenthal W, Birnbaumer M. Structure and chromosomal localization of the human antidiuretic hormone receptor gene. Am J Hum Genet 1992, 51: 1078–83.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Kambouris M, Dlouhy SR, Trofatter JA, Conneally PM, Hodes ME. Localization of the gene for X-linked nephrogenic diabetes insipidus to Xq28. Am J Med Genet 1988, 29: 239–46.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosenthal W, Seibold A, Antaramian A, et al. Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 1992, 359: 233–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Mulders SM, Bichet DG, Rijss JPL, et al. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. J Clin Invest 1988, 102: 57–66.CrossRefGoogle Scholar
  8. 8.
    Kuwahara M, Iwai K, Ooeda T, et al. Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus. Am J Hum Genet 2001, 69: 738–48.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Marr N, Bichet DG, Lonergan M, et al. Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus. Hum Mol Genet 2002, 11: 779–789.PubMedCrossRefGoogle Scholar
  10. 10.
    Morello JP, Bichet DG. Nephrogenic diabetes insipidus. Annu Rev Physiol 2001, 63: 607–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Bichet DG, Fujiwara TM. Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, Vallee D, Childs B, Vogelstein B eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill. 2001, 4181–206Google Scholar
  12. 12.
    Lieburg AF, Verdijk MAJ, Schoute F, et al. Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation. Hum Genet 1995, 96: 70–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Moses MS, Sangani G, Miller JL. Proposed cause of marked vasopressin resistance in a female with an X-linked recessive V2 receptor abnormality. J Clin Endocrinol Metab 1995, 80: 1184–6.PubMedGoogle Scholar
  14. 14.
    Nomura Y, Onigata K, Nagashima T, et al. Detection of skewed X inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab 1997, 82: 3434–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Arthus MF, Lonergan M, Crumley MJ, et al. Report of 33 novel V2R mutations and analysis of 117 families with Xlinked nephrogenic diabetes insipidus. J Am Soc Nephrol 2000, 11: 1044–54.PubMedGoogle Scholar
  16. 16.
    Tilley WD, Marcelli M, Wilson JD, Mcphaul MJ. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A 1989, 86: 327–31.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992, 51: 1229–39.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Knoers NVAM, Deen PMT. Molecular and cellular defects in nephrogenic diabetes insipidus. Pediatr Nephrol 2001, 16: 1146–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Yuasa H, Ito M, Oiso Y, et al. Novel mutations in the V2 vasopressin receptor gene in two pedigrees with congenital nephrogenic diabetes inspidus. J Clin Endocrinol Metab 1994, 79: 361–5.PubMedGoogle Scholar
  20. 20.
    Iwasaki Y, Oiso Y, Kondo K, et al. Aggravation of subclinical diabetes insipidus during pregnancy. N Engl J Med 1991, 324: 522–6.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2004

Authors and Affiliations

  • K. Kinoshita
    • 1
  • Y. Miura
    • 1
  • H. Nagasaki
    • 1
  • T. Murase
    • 1
  • Y. Bando
    • 2
  • Y. Oiso
    • 1
  1. 1.Department of Endocrinology and DiabetologyNagoya University School of MedicineNagoyaJapan
  2. 2.Department of Internal MedicineFukui Saiseikai HospitalFukuiJapan

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