摘要：Background:Phenylketonuria is an inborn metabolic disorder inherited in an autosomal recessive pattern. The detection of pathogenic variations improves the power of at-risk carrier and prenatal detection. We previously found Q375R a novel phenylalanine hydroxylase variation in phenylketonuria patients from the south-west of Iran. Objectives:Here, we aimed to evaluate the rate of the pathogenicity of this novel variant and three other intron variants (IVS9 + 32insA, IVS11 + 163delC, and IVS12 + 30C>T). Methods:The pathogenicity and some structural features of Q375R were analyzed using bioinformatics tools including SIFT, PolyPhen, Mutpred, MutationTaster, nSSNP Analyzer, SNP effect, 3DLigandSite, GeneSplicer, Human Splicing Finder, MaxEntScan, and FSPLICE. Results:According to the SIFT, PolyPhen, Mutpred, and MutationTaster reports, Q375R could be disease-causing. SNAP predicted Q375R as an intermediate damaging variation and nSSNP Analyzer predicted this variation to be neutral. I-Mutant3.0, FoldX, and Mustab showed a decrease in phenylalanine hydroxylase stability upon Q375R alteration. Conclusions:3DLigandSite predicted that phenylalanine hydroxylase binding sites vary in mutant and wild-type proteins. Q375R could be considered an effective factor in the structure and function of phenylalanine hydroxylase. This may be useful in clinical detection of phenylketonuria in Iranian patients and their at-risk relatives. However, we need to do complementary in vitro and in vivo functional assessments for the evaluation and validation of the effects of this variation on phenylalanine hydroxylase function and structure.
