Abstract
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.
Competing interests: None declared
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Acknowledgments
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.
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Communicated by: Maurizio Scarpa, M.D, Ph.D
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Appendices
One-Sentence Take-Home Message
Deep genotyping and bioinformatic approaches can lead to a better understanding of Hunter syndrome (MPSII).
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent for study participation was obtained from all patients included in the study.
This study included 18 Colombian patients with a diagnosis of MPS II whose familial or legal guardians gave informed consent. The informed consent was previously evaluated and approved by the Ethics Committee of the School of Medicine of the National University of Colombia (Comité de Etica de la Facultad de Medicina de la Universidad Nacional de Colombia). By Act Number 16 of November 5, 2010, the Ethics Committee approved the study. After a careful review, the Committee determined that the project meets the ethical requirements and complies with Approbatory Concept. Signed: Prof. CARLOS ARTURO GUERRERO, President of the Ethics Committee.
Conflict of Interest
Johanna Galvis, Jannet González, Alfredo Uribe declare that they have no conflict of interest. Harvy Velasco declares that he received an educative grant from Shire.
Details of the Contribution of Individual Authors
Johanna Galvis: Planning of the work; patients’ recruitment; clinical data extraction and analysis; genotyping steps at laboratory; bioinformatic simulations; reporting of the results; writing and revision of manuscript. Guarantor 1
Jannet Gonzalez: Bioinformatic simulations. Revision of bioinformatic results
Alfredo Uribe: IDS Enzyme assays results, additional clinical data of patients
Harvy Velasco: Planning of the work; patients’ recruitment; clinical data extraction and analysis. Revision of manuscript. Guarantor 2
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Galvis, J., González, J., Uribe, A., Velasco, H. (2014). Deep Genotyping of the IDS Gene in Colombian Patients with Hunter Syndrome. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 19. JIMD Reports, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_376
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DOI: https://doi.org/10.1007/8904_2014_376
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