title: Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations.
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 (G(102)) and rodent (S(102)). 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.
authors: Department of Genetics (MBC-03), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.
authors: Minjing
authors: M
authors: Zou
authors: Essa Y
authors: EY
authors: Baitei
authors: Ali S
authors: AS
authors: Alzahrani
authors: Ranjit S
authors: RS
authors: Parhar
authors: Futwan A
authors: FA
authors: Al-Mohanna
authors: Brian F
authors: BF
authors: Meyer
authors: Yufei
authors: Y
authors: Shi
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