Abstract
Objective: To study the vitamin D receptor (VDR) gene in five Egyptian patients with severe rickets and the clinical features of hereditary vitamin D-resistant rickets, including hypocalcemia, hypophosphatemia, total alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D.
Study design: We amplified and sequenced DNA samples from blood from the patients, their parents, and available family members.
Results: DNA sequence analyses of the VDR gene showed three novel mutations (p.Y295X, p.R343C, and p.R391H) and a previously reported one (p.R30X) in four patients, whereas no mutation was found in one patient. Mutations cosegregated perfectly with affected individuals in all families, and did not exist in unaffected family members or 200 ethnically matched chromosomes.
Conclusion: Three novel deleterious mutations in the VDR ligand-binding domain were identified, which are expected to render the VDR nonfunctional. Successful treatment with frequent high doses of oral calcium and calcidol was evident in all patients; however, hair growth occurred only in one patient.
References
1. Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 1999;20:156–88.Search in Google Scholar
2. Malloy PJ, Pike JW, Feldman D. Hereditary 1,25-dihydroxyvitamin D resistant rickets. In: Feldman D, Pike JW, Glorieux, F, editors. Vitamin D, 2nd ed. San Diego, CA: Elsevier, 2005: 1207–38.Search in Google Scholar
3. Feldman D, Malloy PJ, Krishnan AV, Balint E. Vitamin D: biology, action, and clinical implications. In: Marcus R, Feldman D, Nelson DA, Rosen CJ, editors. Osteoporosis, vol. 3. San Diego: Academic Press, 2007:317–82.Search in Google Scholar
4. Malloy PJ, Wang J, Srivastava T, Feldman D. 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 2010;99:72–9.10.1016/j.ymgme.2009.09.004Search in Google Scholar PubMed PubMed Central
5. Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I. Endocr J 2001;48:427–32.10.1507/endocrj.48.427Search in Google Scholar PubMed
6. Zhou Y, Wang J, Malloy PJ, Dolezel Z, Feldman D. 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 2009;24:643–51.10.1359/jbmr.081216Search in Google Scholar PubMed PubMed Central
7. Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988;242:1702–5.10.1126/science.2849209Search in Google Scholar PubMed
8. Malloy PJ, Zhou Y, Wang J, Hiort O, Feldman D. Hereditary vitamin D-resistant rickets (HVDRR) owing to a heterozygous mutation in the vitamin D receptor. J Bone Miner Res 2011;26:2710–8.10.1002/jbmr.484Search in Google Scholar PubMed
9. Whitfield GK, Selznick SH, Haussler CA, Hsieh JC, Galligan MA, et al. Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D (3): point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner. Mol Endocr 1996;10:1617–31.Search in Google Scholar
10. Mechica JB, Leite MO, Mendonca BB, Frazzatto ES, Borelli A, et al. 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 1997;82:3892–4.10.1210/jcem.82.11.4384Search in Google Scholar PubMed
11. Zhu W, Malloy PJ, Delvin E, Chabot G, Feldman D. Hereditary 1,25-dihydroxyvitamin D-resistant rickets due to an opal mutation causing premature termination of the vitamin D receptor. J Bone Miner Res 1998;13:259–64.10.1359/jbmr.1998.13.2.259Search in Google Scholar PubMed
12. Malloy PJ, Hochberg Z, Tiosano D, Pike JW, Hughes MR, et al. The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families. J Clin Invest 1990;86:2071–9.10.1172/JCI114944Search in Google Scholar PubMed PubMed Central
13. Arita K, Nanda A, Wessagowit V, Akiyama M, Alsaleh QA, et al. A novel mutation in the VDR gene in hereditary vitamin D-resistant rickets. Br J Dermatol 2008;158:168–71.Search in Google Scholar
14. Al-Anzy HM, Alsaleh QA, Salem MT, Nadi H, Sameer E. A new variant of 1,25-dihydroxyvitamin D-receptor-defect rickets and alopecia associated with mental retardation and hearing loss. Gulf J Dermatol 1998;5:30–1.Search in Google Scholar
15. Hochberg Z. Vitamin-D-dependent rickets type 2. Horm Res 2002;58:297–302.10.1159/000066442Search in Google Scholar PubMed
16. Supornsilchai V, Hiranras Y, Wacharasindhu S, Mahayosnond A, Suphapeetiporn K, et al. Two siblings with a novel nonsense mutation, p.R50X, in the vitamin D receptor gene. Endocrine 2011;40:62–6.10.1007/s12020-011-9450-9Search in Google Scholar PubMed
17. Xie Z, Komuves L, Yu QC, Elalieh H, Ng DC, et al. Lack of the vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth. J Invest Dermatol 2002;118:11–6.10.1046/j.1523-1747.2002.01644.xSearch in Google Scholar PubMed
18. Malloy PJ, Feldman D. The role of vitamin D receptor mutations in the development of alopecia. Mol Cell Endocrinol 2011;347:90–6.10.1016/j.mce.2011.05.045Search in Google Scholar PubMed PubMed Central
19. Hewison M, Rut AR, Kristjansson K, Walker RE, Dillon MJ, et al. Tissue resistance to 1,25-dihydroxyvitamin D without a mutation of the vitamin D receptor gene. Clin Endocrinol 1993;39:663–70.10.1111/j.1365-2265.1993.tb02424.xSearch in Google Scholar PubMed
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