Prioritization of Deleterious Variations in the Human Hypoxanthine-Guanine Phosphoribosyltransferase Gene

ABSTRACT Background and Objectives: Non-synonymous single nucleotide polymorphisms are typical genetic variations that may potentially affect the structure or function of expressed proteins, and therefore could be involved in complex disorders. A computational-based analysis has been done to evaluate the phenotypic effect of non-synonymous single nucleotide polymorphisms in the gene encoding the human hypoxanthine-guanine phosphoribosyltransferase (HGPRT-1). HGPRT-1 is an enzyme involved in purine recycling pathway and its deficiency is associated with several human genetic disorders. Methods: We provide a list of all amino acid replacements in the human HGPRT-1 from the dbSNP, Uniprot and dbEST databases. Sorting intolerant from tolerant (SIFT) and PolyPhen softwares were also used in our study. Results: Of 94 amino acid substitutions, rs 267606863 was predicted to be the most deleterious. Substitutions of S110L and S104A in flexible loop and D194N, D201Y, H204R, Y195C, F199V and H204D in hood domain were predicted as functionally damaging. Conclusion: It could be concluded that these intolerant changes may lie within a functional region of the protein and may affect the stability and folding of HGPRT-1. These variants could be used for future functional and molecular epidemiology studies of HGPRT-1-related disorders. Keywords: Polymorphism, Single Nucleotide, Amino acid substitution, Hypoxanthine Phosphoribosyltransferase.