Phenotype prediction for mucopolysaccharidosis type I by in silico analysis
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RESEARCH
Open Access
Phenotype prediction for mucopolysaccharidosis type I by in silico analysis Li Ou1*, Michael J. Przybilla2 and Chester B. Whitley1,2
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: In silico, Single nucleotide polymorphism, Genotype/phenotype correlation, Mucopolysaccharidosis
Background Mucopolysaccharidosis type I (MPS I) is a lysosomal disease included within the genetically heterogeneous group of mucopolysaccharidoses (MPSs). MPS I results from mutations in the gene encoding the lysosomal enzyme α-L-iduronidase (IDUA; glycosaminoglycan a-Liduronohydrolase, OMIM 252800) [1]. Deficiency of IDUA leads to progressive lysosomal accumulation of glycosaminoglycans (GAG) heparan and dermatan sulfate in tissues. Based on the severity of symptoms, MPS I can * Correspondence: [email protected] 1 Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA Full list of author information is available at the end of the article
be divided into three subtypes, from mild (Scheie syndrome, OMIM 607016) to intermediate (Hurler-Scheie syndrome, OMIM 607015) to severe (Hurler syndrome, OMIM 607016). Scheie or Hurler-Scheie patients have symptoms including growth delay, aortic valvular disease, skeletal
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