Deep Genotyping of the IDS Gene in Colombian Patients with Hunter Syndrome

  • Johanna GalvisEmail author
  • Jannet González
  • Alfredo Uribe
  • Harvy Velasco
Research Report
Part of the JIMD Reports book series (JIMD, volume 19)


Background: Mucopolysaccharidosis type II (MPSII), also known as Hunter syndrome, is an X-linked disorder caused by mutations in the iduronate 2 sulfatase (IDS) gene. This enzyme catalyzes the initial step in the catabolism of heparan sulfate and dermatan sulfate; thus, its deficiency leads to the accumulation of these glycosaminoglycans. MPS II has significant allelic heterogeneity, making the establishment of genotype-phenotype correlations difficult. This study assessed clinical features in combination with deep genotyping of a group of Colombian patients with MPS II and attempted to establish a degree of genotype-phenotype correlation by employing bioinformatic tools.

Methods: Eighteen patients were included in this study, 11% of whom were non-neuronopathic, and the other 89% were neuronopathic. Samples were all analyzed using three molecular methodologies: MLPA, direct exon sequencing, and RFLP analysis.

Results: A total of 13 mutations were identified, 6 of which were novel (c.548_564dup16, c.477insT, c.595_607del12, c. 549_562del13, c.182delC, and a complete deletion of exon 7). The frequency of common mutations (R468Q, Q465X, K347Q, K236N, S71N, R88H, and a conversion phenomenon) was 53.85%. The S71N mutation was frequent among the attenuated phenotype, while private frameshift mutations and rearrangements were seen in patients with severe phenotypes. Molecular docking was performed on the wild-type and mutant IDS proteins, which revealed changes in the enzyme-substrate interaction for the mutant IDS.

Conclusion: The frequency of novel mutations (46.15%) is similar to what has been reported elsewhere. The use of bioinformatic tools showed differences in enzyme-substrate interactions. Studies with larger groups of patients are needed.


Bioinformatic analysis Colombian patients Iduronate sulfatase Molecular docking Mucopolysaccharidosis II 



To patients and their families, MRC-Holland for the donation of the MLPA kit for this research, ACOPEL, and Doctors Gabriel Sierra, Luz Norella Correa, Gustavo Contreras, Sandra Mansilla, and Juan Carlos Prieto. To professors Mauricio Rey, Rita Baldrich, Blanca Schroeder, Henry J Rodríguez, and other members of immunogenetics/biology group at Universidad Nacional de Colombia for their support relating to laboratory work. To Tatiana Vinasco, David Serrano, and Andres Gutierrez for contribution of literature and counseling.

Supplementary material

334361_1_En_376_MOESM1_ESM.doc (84 kb)
(DOC 84 kb)


  1. Alves S, Mangas M, Prata MJ et al (2006) Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations. J Inherit Metab Dis 29:743–754CrossRefPubMedGoogle Scholar
  2. Bondeson ML, Dahl N, Malmgren H et al (1995) Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. Hum Mol Genet 4:615–621CrossRefPubMedGoogle Scholar
  3. Brusius-Facchin AC, Schwartz IV, Zimmer C et al (2014) Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients. Mol Genet Metab 111:133–138CrossRefPubMedGoogle Scholar
  4. Bunge S, Steglich C, Zuther C et al (1993) Iduronate-2-sulfatase gene mutations in 16 patients with mucopolysaccharidosis type II (Hunter syndrome). Hum Mol Genet 2:1871–1875CrossRefPubMedGoogle Scholar
  5. Bunge S, Rathmann M, Steglich C et al (1998) Homologous nonallelic recombinations between the iduronate-sulfatase gene and pseudogene cause various intragenic deletions and inversions in patients with mucopolysaccharidosis type II. Eur J Hum Genet 6:492–500CrossRefPubMedGoogle Scholar
  6. Dierks T, Lecca MR, Schlotterhose P, Schmidt B, von Figura K (1999) Sequence determinants directing conversion of cysteine to formylglycine in eukaryotic sulfatases. EMBO J 18:2084–2091PubMedCentralCrossRefPubMedGoogle Scholar
  7. Diez-Roux G, Ballabio A (2005) Sulfatases and human disease. Annu Rev Genomics Hum Genet 6:355–379CrossRefPubMedGoogle Scholar
  8. Froissart R, Maire I, Millat G et al (1998) Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin Genet 53:362–368CrossRefPubMedGoogle Scholar
  9. Froissart R, Da Silva IM, Maire I (2007) Mucopolysaccharidosis type II: an update on mutation spectrum. Acta Paediatr Suppl 96:71–77CrossRefPubMedGoogle Scholar
  10. Galvis J, Gonzalez J, Torrente D, Velasco H, Barreto G (2014) In silico analysis of iduronate 2 sulfatase mutations in Colombian patients with hunter syndrome (MPSII) in: advances in computational biology. Adv Intel Syst Comput 232(2014):205–212CrossRefGoogle Scholar
  11. Gómez A, García-Robles R, Suárez-Obando F (2012) Estimación de las frecuencias de las mucopolisacaridosis y análisis de agrupamiento espacial en los departamentos de Cundinamarca y Boyacá. Biomedica 32:602–609CrossRefPubMedGoogle Scholar
  12. Gucev ZS, Tasic V, Sinigerska I, Kremensky I et al (2011) Hunter syndrome (Mucopolysacharidosis Type II) in Macedonia and Bulgaria. Prilozi 32(2):187–198Google Scholar
  13. Holt J, Poe MD, Escolar ML (2011) Early clinical markers of central nervous system involvement in mucopolysaccharidosis type II. J Pediatr 159(320–326):e322Google Scholar
  14. Isogai K, Sukegawa K, Tomatsu S et al (1998) Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease). J Inherit Metab Dis 21:60–70CrossRefPubMedGoogle Scholar
  15. Jones SA, Almassy Z, Beck M et al (2009) Mortality and cause of death in mucopolysaccharidosis type II-a historical review based on data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 32:534–543CrossRefPubMedGoogle Scholar
  16. Kato T, Kato Z, Kuratsubo I et al (2005) Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II. J Hum Genet 50:395–402CrossRefPubMedGoogle Scholar
  17. Lagerstedt K, Carlberg BM, Karimi-Nejad R, Kleijer WJ, Bondeson ML (2000) Analysis of a 43.6 kb deletion in a patient with Hunter syndrome (MPSII): identification of a fusion transcript including sequences from the gene W and the IDS gene. Hum Mutat 15:324–331CrossRefPubMedGoogle Scholar
  18. Lau C, Lam CW (2008) Molecular investigations of a novel iduronate-2-sulfatase mutant in a Chinese patient. Clin Chim Acta 392:8–10CrossRefPubMedGoogle Scholar
  19. Li P, Thompson JN (1996) Detection of four novel mutations in the iduronate-2-sulphatase gene by single-strand conformation polymorphism analysis of genomic amplicons. J Inher Metab Dis 19(1):93–94CrossRefPubMedGoogle Scholar
  20. Lin SP, Chang JH, Lee-Chen GJ, Lin DS, Lin HY, Chuang CK (2006) Detection of Hunter syndrome (mucopolysaccharidosis type II) in Taiwanese: biochemical and linkage studies of the iduronate-2-sulfatase gene defects in MPS II patients and carriers. Clin Chim Acta 369:29–34CrossRefPubMedGoogle Scholar
  21. Lissens W, Seneca S, Liebaers I (1997) Molecular analysis in 23 Hunter disease families. J Inher Metab Dis 20:453–456CrossRefPubMedGoogle Scholar
  22. Lualdi S, Regis S, Di Rocco M et al (2005) Characterization of iduronate-2-sulfatase gene-pseudogene recombinations in eight patients with Mucopolysaccharidosis type II revealed by a rapid PCR-based method. Hum Mutat 25:491–497CrossRefPubMedGoogle Scholar
  23. Lualdi S, Tappino B, Di Duca M et al (2010) Enigmatic in vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome. Hum Mutat 31:E1261–E1285CrossRefPubMedGoogle Scholar
  24. Malm G, Lund AM, Mansson JE, Heiberg A (2008) Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence. Acta Paediatr 97:1577–1581CrossRefPubMedGoogle Scholar
  25. Martin R, Beck M, Eng C et al (2008) Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 121:e377–e386CrossRefPubMedGoogle Scholar
  26. Miech C, Dierks T, Selmer T, von Figura K, Schmidt B (1998) Arylsulfatase from Klebsiella pneumoniae carries a formylglycine generated from a serine. J Biol Chem 273:4835–4837CrossRefPubMedGoogle Scholar
  27. Millat G, Froissart R, Maire I, Bozon D (1997) Characterization of iduronate sulphatase mutants affecting N-glycosylation sites and the cysteine-84 residue. Biochem J 326(Pt 1):243–247PubMedCentralCrossRefPubMedGoogle Scholar
  28. Nelson J (1997) Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet 101:355–358CrossRefPubMedGoogle Scholar
  29. Neufeld EF, Muenzer J (2001) The mucopolysaccharidoses. In: Scriver CR (ed) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, NYGoogle Scholar
  30. Ochiai T, Suzuki Y, Kato T et al (2007) Natural history of extensive Mongolian spots in mucopolysaccharidosis type II (Hunter syndrome): a survey among 52 Japanese patients. J Eur Acad Dermatol Venereol 21:1082–1085CrossRefPubMedGoogle Scholar
  31. Parkinson EJ, Muller V, Hopwood JJ, Brooks DA (2004) Iduronate-2-sulphatase protein detection in plasma from mucopolysaccharidosis type II patients. Mol Genet Metab 81:58–64CrossRefPubMedGoogle Scholar
  32. Poorthuis BJ, Wevers RA, Kleijer WJ et al (1999) The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105:151–156CrossRefPubMedGoogle Scholar
  33. Rathmann M, Bunge S, Steglich C, Schwinger E, Gal A (1995) Evidence for an iduronate-sulfatase pseudogene near the functional Hunter syndrome gene in Xq27.3-q28. Hum Genet 95:34–38CrossRefPubMedGoogle Scholar
  34. Rathmann M, Bunge S, Beck M, Kresse H, Tylki-Szymanska A, Gal A (1996) Mucopolysaccharidosis type II (Hunter syndrome): mutation “hot spots” in the iduronate-2-sulfatase gene. Am J Hum Genet 59:1202–1209PubMedCentralPubMedGoogle Scholar
  35. Scarpa M, Almassy Z, Beck M et al (2011) Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 6:72PubMedCentralCrossRefPubMedGoogle Scholar
  36. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57PubMedCentralCrossRefPubMedGoogle Scholar
  37. Schwartz IV, Ribeiro MG, Mota JG et al (2007) A clinical study of 77 patients with mucopolysaccharidosis type II. Acta Paediatr Suppl 96:63–70CrossRefPubMedGoogle Scholar
  38. Sohn YB, Ki CS, Kim CH et al (2012) Identification of 11 novel mutations in 49 Korean patients with mucopolysaccharidosis type II. Clin Genet 81:185–190CrossRefPubMedGoogle Scholar
  39. Steen-Bondeson ML, Dahl N, Tonnesen T et al (1992) Molecular analysis of patients with Hunter syndrome: implication of a region prone to structural alterations within the IDS gene. Hum Mol Genet 1:195–198CrossRefPubMedGoogle Scholar
  40. Sukegawa-Hayasaka K, Kato Z, Nakamura H et al (2006) Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: enzymatic activity, protein processing and structural analysis. J Inherit Metab Dis 29:755–761CrossRefPubMedGoogle Scholar
  41. Vafiadaki E, Cooper A, Heptinstall LE, Hatton CE, Thornley M, Wraith JE (1998) Mutation analysis in 57 unrelated patients with MPS II (Hunter’s disease). Arch Dis Child 79:237–241PubMedCentralCrossRefPubMedGoogle Scholar
  42. Villani GR, Daniele A, Balzano N, Di Natale P (2000) Expression of five iduronate-2-sulfatase site-directed mutations. Biochim Biophys Acta 1501(2–3):71–80Google Scholar
  43. Waldow A, Schmidt B, Dierks T, von Bulow R, von Figura K (1999) Amino acid residues forming the active site of arylsulfatase A. Role in catalytic activity and substrate binding. J Biol Chem 274:12284–12288CrossRefPubMedGoogle Scholar
  44. Whitley CB, Anderson RA, Aronovich EL et al (1993) Caveat to genotype-phenotype correlation in mucopolysaccharidosis type II: discordant clinical severity of R468W and R468Q mutations of the iduronate-2-sulfatase gene. Hum Mutat 2(3):235–23Google Scholar
  45. Wilson PJ, Morris CP, Anson DS et al (1990) Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. Proc Natl Acad Sci U S A 87:8531–8535PubMedCentralCrossRefPubMedGoogle Scholar
  46. Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer J (2008a) Initial report from the hunter outcome survey. Genet Med 10:508–516CrossRefPubMedGoogle Scholar
  47. Wraith JE, Scarpa M, Bec M et al (2008b) Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr 167:267–277PubMedCentralCrossRefPubMedGoogle Scholar
  48. Yatziv S, Erickson RP, Epstein CJ (1977) Mild and severe Hunter syndrome (MPS II) within the same sibships. Clin Genet 11:319–326CrossRefPubMedGoogle Scholar
  49. Young ID, Harper PS, Newcombe RG, Archer IM (1982) A clinical and genetic study of Hunter’s syndrome. 2. Differences between the mild and severe forms. J Med Genet 19:408–411PubMedCentralCrossRefPubMedGoogle Scholar
  50. Zhang H, Li J, Zhang X et al (2011) Analysis of the IDS gene in 38 patients with Hunter syndrome: the c.879G > A (p.Gln293Gln) synonymous variation in a female create exonic splicing. PLoS One 6:e22951Google Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Johanna Galvis
    • 1
    Email author
  • Jannet González
    • 2
  • Alfredo Uribe
    • 3
  • Harvy Velasco
    • 4
  1. 1.Master’s Program in Human GeneticsNational University of ColombiaBogotáColombia
  2. 2.Nutrition and Biochemistry LaboratoryPontifical Xaverian UniversityBogotáColombia
  3. 3.Biochemical Investigations Centre (CIBI)University of Los AndesBogotáColombia
  4. 4.Master’s Program in Human GeneticsNational University of ColombiaBogotáColombia

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