In silico analysis of A novel pathogenic variant in an Iranian Mucopolysaccharidosis IIIB patient identified by targeted next-generation sequencing
Iranian Journal of Child Neurology,
Vol. 13 No. 4 (2019),
AbstractMucopolysaccharidosis IIIB (MPS IIIB) (Sanfilippo Syndrome Type B; OMIM 252920) is an autosomal recessive metabolic disorder caused by mutations in the NAGLU gene which encode for lysosomal enzyme N-acetyl-glucosaminidase, involved in degradation of complex polysaccharide, heparan sulfate. The disease characterized by progressive cognitive decline and behavioral difficulties and motor function retardation. In this study, using targeted exome sequencing, we identiﬁed a novel heterozygote deletion variant (c.1294-1304 del CTCTTCCCCAA, p.432LeufsX25) in the NAGLU gene in consanguineous parent of a child who was dying in her 14 years old where the diagnosis of death was Mucopolysaccharidosis. Sanger sequencing was used to confirm the candidate pathogenic variants in extended family members and segregation analysis. Computational docking using the Molegro Virtual Docker (MVD) 6.0.1 software confirmed different affinity binding of truncated protein for its ligand-Acetyl-D-Glucosamine. Moreover, with I-TASSER software functional alterations between wild and mutant proteins evaluated. The variant was classified as pathogenic based on the American College of Medical Genetics and Genomics guideline. This study expands the spectrum of NAGLU pathogenic variants and confirms the utility of targeted NGS sequencing in genetic diagnosis and also the utility and power of additional family information.
- Sanfilippo syndrome type B
- Mucopolysaccharidosis IIIB
- targeted exome sequencing
- NAGLU gene
How to Cite
Zhao HG, Li HH, Bach G, Schmidtchen A, Neufeld EF. The molecular basis of Sanfilippo syndrome type B. Proceedings of the National Academy of Sciences. 1996;93(12):6101-5.
Hara A, Kitazawa N, Taketomi T. Abnormalities of glycosphingolipids in mucopolysaccharidosis type III B. Journal of lipid research. 1984;25(2):175-84.
Weber B, Guo X-H, Kleijer WJ, van de Kamp JJ, Poorthuis BJ, Hopwood JJ. Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. European Journal of Human Genetics. 1999;7(1):34-44.
Bunge S, Knigge A, Steglich C, Kleijer WJ, van Diggelen OP, Beck M, et al. Mucopolysaccharidosis type IIIB (Sanfilippo B): identification of 18 novel α-N-acetylglucosaminidase gene mutations. Journal of medical genetics. 1999;36(1):28-32.
Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. The Journal of pediatrics. 2004;144(5):S27-S34.
Valstar M, Ruijter G, Van Diggelen O, Poorthuis B, Wijburg F. Sanfilippo syndrome: a mini-review. Journal of inherited metabolic disease. 2008;31(2):240-52.
Cleary M, Wraith J. Management of mucopolysaccharidosis type III. Archives of disease in childhood. 1993;69(3):403-406.
Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25(14):1754-60.
Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nature methods. 2010;7(8):575-6.
Hu J, Ng PC. SIFT Indel: predictions for the functional effects of amino acid insertions/deletions in proteins. PloS one. 2013;8(10):e77940.
Folkman L, Yang Y, Li Z, Stantic B, Sattar A, Mort M, et al. DDIG-in: detecting disease-causing genetic variations due to frameshifting indels and nonsense mutations employing sequence and structural properties at nucleotide and protein levels. Bioinformatics. 2015;31(10):1599-606.
Thomsen R, Christensen MH. MolDock: a new technique for high-accuracy molecular docking. Journal of medicinal chemistry. 2006;49(11):3315-21.
Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nature protocols. 2010;5(4):725-38.
Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic acids research. 2014;42(W1):W252-W8.
Kiefer F, Arnold K, Künzli M, Bordoli L, Schwede T. The SWISS-MODEL Repository and associated resources. Nucleic acids research. 2008;37(suppl_1):D387-D92.
Arnold K, Bordoli L, Kopp J, Schwede T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics. 2006;22(2):195-201.
Guex N, Peitsch MC, Schwede T. Automated comparative protein structure modeling with SWISS‐MODEL and Swiss‐PdbViewer: A historical perspective. Electrophoresis. 2009;30(S1): 162-73.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine: official journal of the American College of Medical Genetics. 2015;17(5):405-24.
O'brien JS. Sanfilippo syndrome: profound deficiency of alpha-acetylglucosaminidase activity in organs and skin fibroblasts from type-B patients. Proceedings of the National Academy of Sciences. 1972;69(7):1720-2.
Varki A, Kornfeld S. Identification of a rat liver alpha-N-acetylglucosaminyl phosphodiesterase capable of removing" blocking" alpha-N-acetylglucosamine residues from phosphorylated high mannose oligosaccharides of lysosomal enzymes. Journal of Biological Chemistry. 1980;255(18):8398-401.
Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Human mutation. 2001;18(4):264-81.
Gilkes J, Patterson B, Heldermon C. Mucopolysaccharidosis III. Molecular genetics and genotype-phenotype correlations. OA Genet. 2014; 2: 1-5.
Kamp JVD, Niermeijer M, Figura K, Giesberts M. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C). Clinical genetics. 1981;20(2):152-60.
Andria G, Natale P, Giudice E, Strisciuglio P, Murino P. Sanfilippo B syndrome (MPS III B): mild and severe forms within the same sibship. Clinical genetics. 1979;15(6):500-4.
Beesley C, Jackson M, Young E, Vellodi A, Winchester B. Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB). Journal of inherited metabolic disease. 2005;28(5):759-67.
Valstar MJ, Bruggenwirth HT, Olmer R, Wevers RA, Verheijen FW, Poorthuis BJ, et al. Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic disease. 2010;33(6):759-67.
- Abstract Viewed: 136 times
- PDF Downloaded: 24 times