A novel compound mutation of CYP27B1 in a Chinese family with vitamin D-dependent rickets type 1A
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Wei-Wei Hu
Abstract
Objectives: Mutations in the CYP27B1 gene, which encodes vitamin D 1α-hydroxylase, are the genetic basis of vitamin D-dependent rickets type 1A (VDDR1A, MIM 264700). The aim of this study was to investigate a novel CYP27B1 mutation and its clinical manifestations.
Methods: VDDR1A was diagnosed based on clinical presentation, a physical examination, bone characteristics on an X-ray, and laboratory results. A molecular model of the CYP27B1 protein was constructed using the SWISS-MODEL server and Swiss-PdbViewer.
Results: We sequenced the CYP27B1 gene in a 5-year-old male child who presented with growth retardation and a history of frequent hand, leg, and perioral twitching since the age of 12 months. We identified a compound heterozygous mutation consisting of two missense mutations: one in exon 7 (R389C [c.1165C>T]) and one in exon 8 (R459C [c.1375C>T]). We used the wild-type CYP27B1 as a receptor and calcidiol as a ligand to predict the interaction between the R459 site and calcidiol. According to the predicted structure, the wild-type R459 residue localizes to the pocket where CYP27B1 binds to its ligand.
Conclusions: According to the Human Gene Mutation Database, the compound heterozygous mutation identified in our patient is novel and has not yet been reported in the literature. This mutation provides a new basis for further research on VDDR1A and for the development of clinical diagnostics.
Acknowledgments
This study was supported by the National Science Foundation of China (NSFC) (grant nos. 81370978, 81170803, 30800387, 81070692, and 81000360), STCSM10DZ1950100, and Academic Leaders in Health Sciences in Shanghai (XBR 2011014).
References
1. Holick MF, Chen TC, Lu Z, Sauter E. Vitamin D and skin physiology: a D-lightful story. J Bone Miner Res 2007;22:V28–33.Search in Google Scholar
2. Miller WL. Minireview: regulation of steroidogenesis by electron transfer. Endocrinology 2005;146:2544–50.Search in Google Scholar
3. Miller WL, Portale AA. Vitamin D biosynthesis and vitamin D 1 alpha-hydroxylase deficiency. Endocr Dev 2003;6:156–74.Search in Google Scholar
4. Fu GK, Portale AA, Miller WL. Complete structure of the human gene for the vitamin D 1alpha-hydroxylase, P450c1alpha. DNA Cell Biol 1997;16:1499–507.Search in Google Scholar
5. Scriver CR, Reade TM, DeLuca HF, Hamstra AJ. Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. N Engl J Med 1978:299;976–9.Search in Google Scholar
6. Alzahrani AS, Zou M, Baitei EY, Alshaikh OM, Al-Rijjal RA, et al. A novel G102E mutation of CYP27B1 in a large family with vitamin D-dependent rickets type 1. J Clin Endocrinol Metab 2010:95;4176–83.Search in Google Scholar
7. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, et al. Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92:3177–82.Search in Google Scholar
8. Kitanaka S, Katsumata N, Tanae A, Hibi I, Takeyama K, et al. A new compound heterozygous mutation in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. J Clin Endocrinol Metab 1997;82:4054–8.Search in Google Scholar
9. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, et al. Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 1998;338:653–61.Search in Google Scholar
10. Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, et al. Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families. Am J Hum Genet 1998;63:1694–702.Search in Google Scholar
11. Cui N, Xia W, Su H, Pang L, Jiang Y, et al. Novel mutations of CYP27B1 gene lead to reduced activity of 1alpha-hydroxylase in Chinese patients. Bone 2012;53:563–9.Search in Google Scholar
12. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9.Search in Google Scholar
13. Zou M, Baitei EY, Alzahrani AS, Parhar RS, Al-Mohanna FA, et al. Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations. Endocrine 2011;40:14–20.Search in Google Scholar
14. Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL workspace: a Web-based environment for protein structure homology modelling. Bioinformatics 2006;22:195–201.Search in Google Scholar
15. Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res 2003;31:3381–5.Search in Google Scholar
16. Durmaz E, Zou M, Al-Rijjal RA, Bircan I, Akçurin S, et al. Clinical and genetic analysis of patients with vitamin D-dependent rickets type 1A. Clin Endocrinol (Oxf) 2012;77:363–9.Search in Google Scholar
17. Wang X, Zhang MY, Miller WL, Portale AA. Novel gene mutations in patients with 1alpha-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 2002;87:2424–30.Search in Google Scholar
18. Smith SJ, Rucka AK, Berry JL, Davies M, Mylchreest S, et al. Novel mutations in the 1alpha-hydroxylase (P450c1) gene in three families with pseudovitamin D-deficiency rickets resulting in loss of functional enzyme activity in blood-derived macrophages. J Bone Miner Res 1999;14:730–9.Search in Google Scholar
19. Hu R, Liu W, Li H, Yang L, Chen C, et al. A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem 2011;286:12328–39.Search in Google Scholar
20. Li H, Xie H, Liu W, Hu R, Huang B, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 2009;119:3666–77.Search in Google Scholar
21. Sierk ML, Pearson WR. Sensitivity and selectivity in protein structure comparison. Protein Sci 2004;13:773–85.Search in Google Scholar
22. Kolodny R, Koehl P, Levitt M. Comprehensive evaluation of protein structure alignment methods: scoring by geometric measures. J Mol Biol 2005;346:1173–88.Search in Google Scholar
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