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Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations

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Abstract

Vitamin D-dependent rickets type 1 (VDDR-I) is caused by mutation in CYP27B1. The glycine residue at codon 102 is not conserved between human (G102) and rodent (S102). G102E mutation results in 80% reduction in its enzymatic activity but PolyPhen predicts benign change. It is not known whether G102S has any damaging effect on 1α-hydroxylase activity. We investigated the effect of CYP27B1 G102S on its enzymatic activity and compared mutation prediction accuracy for all known CYP27B1 mutations among three free online protein prediction programs: PolyPhen, PolyPhen-2, and PSIPRED. G102S has no damaging effect on 1α-hydroxylase activity. G102D retained 30% enzymatic activity. All three programs correctly predicted damaging change for G102D. PolyPhen predicted benign change for G102S, whereas PolyPhen-2 and PSIPRED indicated possible damaging effect. Among 24 reported damaging mutations, PSIPRED, PolyPhen-2, and PolyPhen achieved 100%, 91.7% (22/24), and 75% (18/24) accuracy rate, respectively. The residues of incorrectly predicted mutations were not conserved. We conclude that G102D resulted in a significant reduction in 1α-hydroxylase activity, whereas G102S did not. PSIPRED and PolyPhen-2 are superior to PolyPhen in predicting damaging mutations.

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Acknowledgments

This study was funded by a grant from National Comprehensive Plan for Science & Technology.

Conflicts of interest

All authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Genetics (MBC-03), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia

    Minjing Zou, Essa Y. Baitei, Brian F. Meyer & Yufei Shi

  2. Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

    Ali S. Alzahrani

  3. Department of Biological and Medical Research, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

    Ranjit S. Parhar & Futwan A. Al-Mohanna

Authors
  1. Minjing Zou
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  2. Essa Y. Baitei
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  5. Futwan A. Al-Mohanna
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  6. Brian F. Meyer
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  7. Yufei Shi
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Correspondence to Yufei Shi.

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Zou, M., Baitei, E.Y., Alzahrani, A.S. et al. Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations. Endocrine 40, 14–20 (2011). https://doi.org/10.1007/s12020-011-9489-7

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  • DOI: https://doi.org/10.1007/s12020-011-9489-7

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