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Mutation update and long-term outcome after treatment with active vitamin D3 in Chinese patients with pseudovitamin D-deficiency rickets (PDDR)

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Abstract

Summary

Pseudovitamin D-deficiency rickets is a rare disease which is caused by CYP27B1. In this study, we identified 9 mutations in 7 PDDR patients. In addition, we observed the response to long-term treatment of calcitriol in 15 Chinese patients with PDDR, which showed that the biochemical abnormalities had been corrected satisfactorily after 1-year treatment.

Introduction

Pseudovitamin D-deficiency rickets is a rare autosomal recessive disorder resulting from a defect in 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by CYP27B1. The purpose of this study was to identify the CYP27B1 mutations and investigate the response to long-term treatment of calcitriol in Chinese patients with PDDR.

Methods

We investigated CYP27B1 mutations in seven individuals from six separate families. To investigate the response to long-term (13 years) treatment with calcitriol in PDDR patients, we additionally collected clinical data of eight families from our previous report and analyzed their biochemical parameter and radiographic changes during the treatment.

Results

Nine different mutations were identified: two novel missense mutations (G194R, R259L), three novel and one reported deletion mutations (c1442delA, c1504delA, c311-321del, and c. 48-60del), two novel nonsense mutations (c.85G>T, c.580G>T), and a reported insertion mutation (c1325-1332insCCCACCC). The statistical analysis revealed that parathyroid hormone (PTH) and ALP significantly decreased after 6-month and 1-year treatment with calcitriol respectively. Urine calcium was measured in all the patients without kidney stones being documented. After 6-year treatment, the radiographic abnormalities had also been improved. Two patients who had reached their final height are both with short stature (height Z-score below − 2.0).

Conclusions

We identified seven novel mutations of CYP27B1 gene in seven Chinese PDDR families. Our findings revealed after 1-year treatment of active vitamin D3, PTH and ALP significantly decreased. The correction of the biochemical abnormalities had not improved the final height satisfactorily.

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References

  1. Bikle DD (2010) Vitamin D: newly discovered actions require reconsideration of physiologic requirements. Trends Endocrinol Metab 21:375–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ponchon G, Kennan AL, Deluca HF (1969) “Activation” of vitamin D by the liver. J Clin Invest 48:2032–2037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Prosser DE, Jones G (2004) Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci 29:664–673

    Article  CAS  PubMed  Google Scholar 

  4. Sakaki T, Kagawa N, Yamamoto K, Inouye K (2005) Metabolism of vitamin D3 by cytochromes P450. Front Biosci 10:119–134

    Article  CAS  PubMed  Google Scholar 

  5. Zehnder D, Bland R, Williams MC, et al. 2001 Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86(2):888-894

  6. Michael F, Holick (2006) Resurrection of vitamin D deficiency and rickets. J Clin Invest 116(8):2062–2072

    Article  CAS  Google Scholar 

  7. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanagisawa J, Tanaka T, Kato S (1998) Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 338:653–661

    Article  CAS  PubMed  Google Scholar 

  8. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA (2007) Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 92:3177–3182

    Article  CAS  PubMed  Google Scholar 

  9. Ningyi C, Weibo X, Hua S, Li P et al (2012) Novel mutations of CYP27B1 gene lead to reduced activity of 1α-hydroxylase in Chinese patients. Bone 51:563–569

    Article  CAS  Google Scholar 

  10. Scriver CR, Reade TM, Deluca HF, Hamstra AJ (1978) Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. N Engl J Med 299:976–979

    Article  CAS  PubMed  Google Scholar 

  11. Wang X, Zhang MY, Miller WL, Portale AA (2002) Novel gene mutations in patients with 1alpha-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 87:2424–2430

    CAS  PubMed  Google Scholar 

  12. Kim CJ, Kaplan LE, Perward F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA (2007) Vitamin D 1α-hydroxylase gene mutations in patients with 1α-hydroxylase deficiency. J Clin Endocrinol Metab 92:3177–3182

    Article  CAS  PubMed  Google Scholar 

  13. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA (2007) Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 92:3177–3182

    Article  CAS  PubMed  Google Scholar 

  14. Alzahrani Ali S, Zou M, Baitei EY (2010) A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1. J Clin Endocrinol Metab 95:4176–4183

    Article  CAS  PubMed  Google Scholar 

  15. E D, Zou M, Al-Rijjal RA, Bircan I, Akçurin S, Meyer B, Shi Y (2012) Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. Clin Endocrinol 77(3):363–369

    Article  CAS  Google Scholar 

  16. Durmaz E, Zou M, Al-Rijjal RA, Bircan I, Akçurin S, Meyer B, Shi Y (2012) Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. Clin Endocrinol (Oxf) 77(3):363–369

    Article  CAS  Google Scholar 

  17. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, Deluca HF (1973) Pathogenesis of hereditary vitamin D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1α,25-dihydroxyvitamin D. N Engl J Med 289:817–822

    Article  CAS  PubMed  Google Scholar 

  18. Porcu L, Meloni A, Casula L, Asunis I, Marini MG, Cao A, Moi P (2002) A novel splicing defect (IVS6+1G>T) in a patient with pseudovitamin D deficiency rickets. J Endocrinol Investig 25:557–560

    Article  CAS  Google Scholar 

  19. Anderson PH, Hendrix I, Sawyer RK, Zarrinkalam R, Manavis J, Sarvestani GT, May BK, Morris HA (2008) Co-expression of CYP27B1 enzyme with the 1.5kb CYP27B1promoter-luciferase transgene in the mouse. Mol Cell Endocrinol 285:1–9

    Article  CAS  PubMed  Google Scholar 

  20. Edouard T, Alos N, Chabot G, Roughley P, Glorieux FH, Rauch F (2011) Short- and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. J Clin Endocrinol Metab 96(1):82–89

    Article  CAS  PubMed  Google Scholar 

  21. Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA, Miller WL (1998) Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet 63(6):1694–1702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamamotoa K, Masunoa H, Sawada N, Sakaki K, Inouye K, Ishiguro M, Yamada S 2004 Homology modeling of human 25 hydroxyvitamin D3 1α hydroxylase(CYP27B1) based on the crystal structure of rabbit CYP2C5 J Steroid Biochem Mol Biol 89–90:167–171

  23. Yamamoto K, Uchida E, Urushino N et al (2005) Identification of the amino acid residue of CYP27B1 responsible for binding of 25-hydroxyvitamin D3 whose mutation causes vitamin D-dependent rickets type 1. J Biol Chem 280:30511–30516

    Article  CAS  PubMed  Google Scholar 

  24. Adams JS, Kantorovich V, Wu C, Javanbakht M, Hollis BW (1999) Resolution of vitamin D insufficiency in osteopenic patients results in rapid recovery of bone mineral density. J Clin Endocrinol Metab 84:2729–2730

    CAS  PubMed  Google Scholar 

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Acknowledgments

We appreciate our patients and their families for their participating in this study.

Funding

This study was supported by a grant from The Ministry of Science and Technology of the Peoples Republic of China (National Science and Technology Major Projects for Major New Drugs Innovation and Development 2008ZX09312-016), National Natural Science Foundation of China (No. 81070687, 81170805, and 81670714), Beijing Natural Science Foundation (No. 7121012) and Scientific Research Foundation of Beijing Medical Development (No. 2007-3029), National Key Program of Clinical Science (WBYZ2011-873), and CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-3-003).

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Authors and Affiliations

  1. Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No. 1, Wangfujing, Dongcheng District, Beijing, 100730, China

    Y. Chi, J. Sun, L. Pang, R. Jiajue, Y. Jiang, O. Wang, M. Li, X. Xing, Y. Hu, X. Zhou, X. Meng & W. Xia

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  1. Y. Chi
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  2. J. Sun
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  3. L. Pang
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  6. O. Wang
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  7. M. Li
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  9. Y. Hu
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  11. X. Meng
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  12. W. Xia
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Corresponding author

Correspondence to W. Xia.

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This study was approved by the Department of Scientific Research at Peking Union Medical College Hospital. Written informed consent was obtained from the patients and their family members included in this study.

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Chi, Y., Sun, J., Pang, L. et al. Mutation update and long-term outcome after treatment with active vitamin D3 in Chinese patients with pseudovitamin D-deficiency rickets (PDDR). Osteoporos Int 30, 481–489 (2019). https://doi.org/10.1007/s00198-018-4607-5

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  • DOI: https://doi.org/10.1007/s00198-018-4607-5

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