Skip to main content

Advertisement

SpringerLink
Log in

Two siblings with a novel nonsense mutation, p.R50X, in the vitamin D receptor gene

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disorder caused by inactivating mutations in the vitamin D receptor (VDR) gene. We identified two affected children from the same family, one at the age of 10 years and 9 months and the other at 9 months old. Mutation analysis by PCR-sequencing the entire coding region of the VDR gene revealed a homozygous C to T transition in exon 2 of the VDR gene (c.148C>T) resulting in a stop codon at amino acid position 50 (p.R50X) in the proband and his younger sister. The p.R50X has never been previously described. Both asymptomatic parents were heterozygous for the mutation. In addition to most of the clinical features of HVDRR including total alopecia, symptoms of hypocalcemia at a later onset and normophosphatemia, rarely found in HVDRR were present in the proband. This study also emphasizes an important role of genetic testing for early diagnosis and genetic counseling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

HVDRR:

Hereditary vitamin D-resistant rickets

VDR:

Vitamin D receptor

PTH:

Parathyroid hormone

References

  1. M.R. Hughes, P.J. Malloy, D.G. Kieback, R.A. Kesterson, J.W. Pike, D. Feldman, B.W. O’Malley, Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242, 1702–1705 (1988)

    Article  PubMed  CAS  Google Scholar 

  2. H.H. Ritchie, M.R. Hughes, E.T. Thompson, P.J. Malloy, Z. Hochberg, D. Feldman, J.W. Pike, B.W. O’Malley, An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families. Proc. Natl. Acad. Sci. USA 86, 9783–9787 (1989)

    Article  PubMed  CAS  Google Scholar 

  3. P.J. Malloy, J.W. Pike, D. Feldman, The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr. Rev. 20, 156–188 (1999)

    Article  PubMed  CAS  Google Scholar 

  4. M.H. Brooks, N.H. Bell, L. Love, P.H. Stern, E. Orfei, S.F. Queener, A.J. Hamstra, H.F. DeLuca, Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25-dihydroxyvitamin D. N. Engl. J. Med. 298, 996–999 (1978)

    Article  PubMed  CAS  Google Scholar 

  5. H. Yagi, K. Ozono, H. Miyake, K. Nagashima, T. Kuroume, J.W. Pike, A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J. Clin. Endocrinol. Metab. 76, 509–512 (1993)

    Article  PubMed  CAS  Google Scholar 

  6. Z. Hochberg, Vitamin-D-dependent rickets type 2. Horm. Res. 58, 297–302 (2002)

    Article  PubMed  CAS  Google Scholar 

  7. M.R. Haussler, C.A. Haussler, P.W. Jurutka, P.D. Thompson, J.C. Hsieh, L.S. Remus, S.H. Selznick, G.K. Whitfield, The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J. Endocrinol. 154, S57–S73 (1997)

    Article  PubMed  CAS  Google Scholar 

  8. P. Katavetin, P. Katavetin, S. Wacharasindhu, V. Shotelersuk, A girl with a novel splice site mutation in VDR supports the role of a ligand-independent VDR function on hair cycling. Horm. Res. 66, 273–276 (2006)

    Article  PubMed  CAS  Google Scholar 

  9. K. Kristjansson, A.R. Rut, M. Hewison, J.L. O’Riordan, M.R. Hughes, Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3. J. Clin. Investig. 92, 12–16 (1993)

    Article  PubMed  CAS  Google Scholar 

  10. R.J. Wiese, H. Goto, J.M. Prahl, S.J. Marx, M. Thomas, A. Al-Aqeel, H.F. De Luca, Vitamin D-dependency rickets type II: truncated vitamin D receptor in three kindreds. Mol. Cell. Endocrinol. 90, 197–201 (1993)

    Article  PubMed  CAS  Google Scholar 

  11. F.J. Cockerill, N.S. Hawa, N. Yousaf, M. Hewison, J.L. O’Riordan, S.M. Farrow, Mutations in the vitamin D receptor gene in three kindreds associated with hereditary vitamin D resistant rickets. J. Clin. Endocrinol. Metab. 82, 3156–3160 (1997)

    Article  PubMed  CAS  Google Scholar 

  12. J.B. Mechica, M.O. Leite, B.B. Mendonca, E.S. Frazzatto, A. Borelli, A.C. Latronico, A novel nonsense mutation in the first zinc finger of the vitamin D receptor causing hereditary 1,25-dihydroxyvitamin D3-resistant rickets. J. Clin. Endocrinol. Metab. 82, 3892–3894 (1997)

    Article  PubMed  CAS  Google Scholar 

  13. W. Zhu, P.J. Malloy, E. Delvin, G. Chabot, D. Feldman, Hereditary 1,25-dihydroxyvitamin D-resistant rickets due to an opal mutation causing premature termination of the vitamin D receptor. J. Bone Miner. Res. 13, 259–264 (1998)

    Article  PubMed  CAS  Google Scholar 

  14. P.J. Malloy, W. Zhu, R. Bouillon, D. Feldman, A novel nonsense mutation in the ligand binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. Mol. Genet. Metab. 77, 314–318 (2002)

    Article  PubMed  CAS  Google Scholar 

  15. Y. Zhou, J. Wang, P.J. Malloy, Z. Dolezel, D. Feldman, Compound heterozygous mutations in the vitamin D receptor in a patient with hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia. J. Bone Miner. Res. 24, 643–651 (2009)

    Article  PubMed  CAS  Google Scholar 

  16. S. Beer, M. Tieder, D. Kohelet, O.A. Liberman, E. Vure, G. Bar-Joseph, D. Gabizon, Z.U. Borochowitz, M. Varon, D. Modai, Vitamin D resistant rickets with alopecia: a form of end organ resistance to 1,25 dihydroxy vitamin D. Clin. Endocrinol. (Oxf) 14, 395–402 (1981)

    Article  CAS  Google Scholar 

  17. S.J. Marx, M.M. Bliziotes, M. Nanes, Analysis of the relation between alopecia and resistance to 1,25-dihydroxyvitamin D. Clin. Endocrinol. (Oxf) 25, 373–381 (1986)

    Article  CAS  Google Scholar 

  18. P.J. Malloy, W. Zhu, X.Y. Zhao, G.B. Pehling, D. Feldman, A novel inborn error in the ligand-binding domain of the vitamin D receptor causes hereditary vitamin D-resistant rickets. Mol. Genet. Metab. 73, 138–148 (2001)

    Article  PubMed  CAS  Google Scholar 

  19. J. Miller, K. Djabali, T. Chen, Y. Liu, M. Ioffreda, S. Lyle, A.M. Christiano, M. Holick, G. Cotsarelis, Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J. Investig. Dermatol. 117, 612–617 (2001)

    Article  PubMed  CAS  Google Scholar 

  20. R. Bergman, R. Schein-Goldshmid, Z. Hochberg, O. Ben-Izhak, E. Sprecher, The alopecias associated with vitamin D-dependent rickets type IIA and with hairless gene mutations: a comparative clinical, histologic, and immunohistochemical study. Arch. Dermatol. 141, 343–351 (2005)

    Article  PubMed  Google Scholar 

  21. J.C. Hsieh, J.M. Sisk, P.W. Jurutka, C.A. Haussler, S.A. Slater, M.R. Haussler, C.C. Thompson, Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J. Biol. Chem. 278, 38665–38674 (2003)

    Article  PubMed  CAS  Google Scholar 

  22. P.J. Malloy, R. Xu, A. Cattani, L. Reyes, D. Feldman, A unique insertion/substitution in helix H1 of the vitamin D receptor ligand binding domain in a patient with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J. Bone Miner. Res. 19, 1018–1024 (2004)

    Article  PubMed  CAS  Google Scholar 

  23. P.J. Malloy, R. Xu, L. Peng, S. Peleg, A. Al-Ashwal, D. Feldman, Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology 145, 5106–5114 (2004)

    Article  PubMed  CAS  Google Scholar 

  24. G.K. Whitfield, S.H. Selznick, C.A. Haussler, J.C. Hsieh, M.A. Galligan, P.W. Jurutka, P.D. Thompson, S.M. Lee, J.E. Zerwekh, M.R. Haussler, Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner. Mol. Endocrinol. 10, 1617–1631 (1996)

    Article  PubMed  CAS  Google Scholar 

  25. P.J. Malloy, R. Xu, L. Peng, P.A. Clark, D. Feldman, A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Mol. Endocrinol. 16, 2538–2546 (2002)

    Article  PubMed  CAS  Google Scholar 

  26. N.S. Ma, P.J. Malloy, P. Pitukcheewanont, D. Dreimane, M.E. Geffner, D. Feldman, Hereditary vitamin D resistant rickets: identification of a novel splice site mutation in the vitamin D receptor gene and successful treatment with oral calcium therapy. Bone 45, 743–746 (2009)

    Article  PubMed  CAS  Google Scholar 

  27. P.J. Malloy, D. Feldman, Genetic disorders and defects in vitamin D action. Endocrinol. Metab. Clin. North Am. (2010) 39, 333–346

    Google Scholar 

  28. P.J. Malloy, J. Wang, T. Srivastava, D. Feldman, Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor. Mol. Genet. Metab. 99, 72–79 (2010)

    Article  PubMed  CAS  Google Scholar 

  29. Y. Weisman, I. Bab, D. Gazit, Z. Spirer, M. Jaffe, Z. Hochberg, Long-term intracaval calcium infusion therapy in end-organ resistance to 1,25-dihydroxyvitamin D. Am. J. Med. 83, 984–990 (1987)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank the patients and their family for participation in this study. We are grateful to Chalurmpon Srichomthong and Siriprapa Tongkobpech for technical assistance. This study was supported by the Faculty of Medicine, Chulalongkorn University, National Science and Technology Development Agency, the Thailand Research Fund, the National Research University Project of CHE and the Ratchadapiseksomphot Endowment Fund (HR1163A).

Author information

Authors and Affiliations

  1. Division of Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Vichit Supornsilchai, Yodporn Hiranras & Suttipong Wacharasindhu

  2. Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Atchara Mahayosnond

  3. Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Kanya Suphapeetiporn & Vorasuk Shotelersuk

  4. Molecular Genetics Diagnostic Center, King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, 10330, Thailand

    Kanya Suphapeetiporn & Vorasuk Shotelersuk

  5. Division of Genetics and Metabolism, Department of Pediatrics, Chulalongkorn University, Sor Kor building 11th floor, Bangkok, 10330, Thailand

    Kanya Suphapeetiporn

Authors
  1. Vichit Supornsilchai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yodporn Hiranras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suttipong Wacharasindhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atchara Mahayosnond
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kanya Suphapeetiporn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vorasuk Shotelersuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kanya Suphapeetiporn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Supornsilchai, V., Hiranras, Y., Wacharasindhu, S. et al. Two siblings with a novel nonsense mutation, p.R50X, in the vitamin D receptor gene. Endocrine 40, 62–66 (2011). https://doi.org/10.1007/s12020-011-9450-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-011-9450-9

Keywords

Search

Navigation