A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations

Abstract

A fundamental goal of medical genetics is the accurate prediction of genotype–phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/HA_Predict/index.htm.

In silico analyses of missense mutations in coagulation factor VIII: identification of severity determinants of haemophilia A

“…In recent years researchers have utilized various in silico approaches to assess the consequences of missense mutations in several diseases [13,14,18,[33][34][35][36]. Missense variations could have different fates contingent upon a variety of sequence and structural contexts, and thus are the most challenging in this regard.…”

Analysis of the VSX1 gene in sporadic keratoconus patients from China

“…The in silico prediction programs Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/) and PROVEAN (http://provean.jcvi.org/index.php) were used to predict the effect of the VSX1 gene sequence variants on protein structure and function [22–24]. …”

Computational prediction of phenotype in haemophilia A

“…These approaches have mainly looked at the impact of novel non-synonymous F8 SNPs from clinical cohorts [12][13][14][15][16]. More recently published in-silico data have evaluated prediction of deleterious effect of F8 SNPs [17,18]. Although providing interesting insights into the likely mechanism of disruption of FVIII structure, these studies have not provided clear data to correlate genotype and phenotype.…”

“…A large study of 640 point mutations, including mutations associated with variable phenotype, identified structural alterations that generally correlated with a severe or non-severe phenotype using homology modelling and evaluation of evolutionary significance [3]. Of these, Hamasaki-Katagari et al have recently presented a tool (HApredictor) demonstrating high sensitivity and specificity for prediction of the deleterious effect of F8 SNPs (non-synonymous and synonymous), although this was not able to predict phenotype [18]. More recently published in-silico data have evaluated prediction of deleterious effect of F8 SNPs [17,18].…”