%0 Journal Article
%T Regression Modeling and Meta-Analysis of Diagnostic Accuracy of SNP-Based Pathogenicity Detection Tools for UGT1A1 Gene Mutation
%A Fakher Rahim
%A Hamid Galehdari
%A Javad Mohammadi-asl
%A Najmaldin Saki
%J Genetics Research International
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/546909
%X Aims. This review summarized all available evidence on the accuracy of SNP-based pathogenicity detection tools and introduced regression model based on functional scores, mutation score, and genomic variation degree. Materials and Methods. A comprehensive search was performed to find all mutations related to Crigler-Najjar syndrome. The pathogenicity prediction was done using SNP-based pathogenicity detection tools including SIFT, PHD-SNP, PolyPhen2, fathmm, Provean, and Mutpred. Overall, 59 different SNPs related to missense mutations in the UGT1A1 gene, were reviewed. Results. Comparing the diagnostic OR, our model showed high detection potential (diagnostic OR: 16.71, 95% CI: 3.38¨C82.69). The highest MCC and ACC belonged to our suggested model (46.8% and 73.3%), followed by SIFT (34.19% and 62.71%). The AUC analysis showed a significance overall performance of our suggested model compared to the selected SNP-based pathogenicity detection tool ( ). Conclusion. Our suggested model is comparable to the well-established SNP-based pathogenicity detection tools that can appropriately reflect the role of a disease-associated SNP in both local and global structures. Although the accuracy of our suggested model is not relatively high, the functional impact of the pathogenic mutations is highlighted at the protein level, which improves the understanding of the molecular basis of mutation pathogenesis. 1. Introduction Crigler-Najjar syndrome (CNS) (MIM nos. 218800, 606785) type I and type II are inherited as autosomal recessive conditions that is resulted from mutations in the UGT1A1 gene (UGT1A1; MIM nos. 191740) [1¨C4]. Type I is characterized by almost complete absence of UGT1A1 enzyme activity, and these patients are refractory to phenobarbital treatment, while type II is a less severe form of deficiency [5, 6]. Patients with CNS are at permanent risk of developing severe neurologic complications such as hearing problems, mental retardation, and choreoathetosis due to severe unconjugated hyperbilirubinemia [7]. It is well known that UGT1A1 is expressed specifically in the liver and that it is difficult to perform an expression analysis directly on the patients by invasive liver biopsy but to state that the mutation causes inactivation of the enzyme you could perform an in vitro functional study by cloning the mutated cDNA of UGT1A1 in an expression vector. The constructs could be transfected in hepatic cell lines as HepG2 or HUH7. The expression analysis on these cells overexpressing the mutated forms of UGT1A1 will allow you to finally demonstrate the
%U http://www.hindawi.com/journals/gri/2013/546909/