Phenotype prediction for mucopolysaccharidosis type I by in silico analysis

Abstract

Background: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease due to deficiency of α-L-iduronidase (IDUA), a lysosomal enzyme that degrades glycosaminoglycans (GAG) heparan and dermatan sulfate. To achieve optimal clinical outcomes, early and proper treatment is essential, which requires early diagnosis and phenotype severity prediction.

Results: To establish a genotype/phenotype correlation of MPS I disease, a combination of bioinformatics tools including SIFT, PolyPhen, I-Mutant, PROVEAN, PANTHER, SNPs&GO and PHD-SNP are utilized. Through analyzing single nucleotide polymorphisms (SNPs) by these in silico approaches, 28 out of 285 missense SNPs were predicted to be damaging. By integrating outcomes from these in silico approaches, a prediction algorithm (sensitivity 94%, specificity 80%) was thereby developed. Three dimensional structural analysis of 5 candidate SNPs (P533R, P496R, L346R, D349G, T374P) were performed by SWISS PDB viewer, which revealed specific structural changes responsible for the functional impacts of these SNPs. Additionally, SNPs in the untranslated region were analyzed by UTRscan and PolymiRTS. Moreover, by investigating known pathogenic mutations and relevant patient phenotypes in previous publications, phenotype severity (severe, intermediate or mild) of each mutation was deduced.

Conclusions: Collectively, these results identified potential candidate SNPs with functional significance for studying MPS I disease. This study also demonstrates the effectiveness, reliability and simplicity of these in silico approaches in addressing complexity of underlying genetic basis of MPS I disease. Further, a step-by-step guideline for phenotype prediction of MPS I disease is established, which can be broadly applied in other lysosomal diseases or genetic disorders.

Keywords: Genotype/phenotype correlation; In silico; Mucopolysaccharidosis; Single nucleotide polymorphism.

Fig. 1

Superimposed structure of native protein with modeled mutant protein for D349G. a Overall structure of the superimposed model. Native protein in white (cartoon shape), mutant protein in green, wild type residue (Asp349) in red, and mutated residue (Gly349) in yellow. b close-up view of the superimpose model. Main protein backbone in white, wild type reside (Asp349) in red, mutated residue (Gly349) in yellow, a chloride anion in green

Fig. 2

Close-up view of superimposed structure of native and mutant residues (a P496R; b P533R; c T374P; d L346R). The main protein core is shown in white color while the wild type and mutated residues are shown in red and yellow color, respectively

Fig. 3

Step-by-step guideline for phenotype prediction by in silico analysis