Genetic Analysis of 17 Children with Hunter Syndrome: Identification and Functional Characterization of Four Novel Mutations in the Iduronate-2-Sulfatase Gene

Dimitry A. Chistiakov; Lyudmila M. Kuzenkova; Kirill V. Savost'anov; Anait K. Gevorkyan; Alexander A. Pushkov; Alexey G. Nikitin; Nato D. Vashakmadze; Natalia V. Zhurkova; Tatiana V. Podkletnova; Leila S. Namazova-Baranova; Alexander A. Baranov

doi:10.1016/j.jgg.2014.01.007

Volume 41 Issue 4

Apr. 2014

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Article Navigation > Journal of Genetics and Genomics > 2014 > 41(4): 197-203

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Genetic Analysis of 17 Children with Hunter Syndrome: Identification and Functional Characterization of Four Novel Mutations in the Iduronate-2-Sulfatase Gene

doi: 10.1016/j.jgg.2014.01.007

a
Department of Medical Nanobiotechnology, Pirogov Russian State Medical University, Moscow 117997, Russia
b
Department of Molecular and Genetic Diagnostics, Division of Laboratory Medicine, Institute of Pediatrics, Research Center for Children's Health, Moscow 119991, Russia
c
Department of Psychoneurology and Psychosomatic Pathology, Institute of Pediatrics, Research Center for Children's Health, Moscow 119991, Russia
d
Institute of Preventive Pediatrics and Rehabilitation, Research Center for Children's Health, Moscow 119991, Russia
e
Research Center for Children's Health, Moscow 119991, Russia

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Corresponding author: E-mail address: dmitry.chistyakov@yahoo.com (Dimitry A. Chistiakov)
Received Date: 2013-10-27
Accepted Date: 2014-01-26
Rev Recd Date: 2014-01-21

Available Online: 2014-02-04

Publish Date: 2014-04-20

Abstract

Abstract

Mucopolysaccharidosis type II (MPS II) is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase (IDS) gene. In this study, IDS activity in peripheral mononuclear blood monocytes (PMBCs) was measured with a fluorimetric enzyme assay. Urinary glycosaminoglycans (GAGs) were quantified using a colorimetric assay. AllIDS exons and intronic flanks were bidirectionally sequenced. A total of 15 mutations (all exonic region) were found in 17 MPS II patients. In this cohort of MPS II patients, all alterations in the IDS gene were caused by point nucleotide substitutions or small deletions. Mutations p.Arg88His and p.Arg172* occurred twice. All mutations were inherited except for p.Gly489Alafs*7, a germline mutation. We found four new mutations (p.Ser142Phe, p.Arg233Gly, p.Glu430*, and p.Ile360Tyrfs*31). In Epstein-Barr virus (EBV)-immortalized PMBCs derived from the MPS II patients, no IDS protein was detected in case of the p.Ser142Phe and p.Ile360Tyrfs*31 mutants. For p.Arg233Gly and p.Glu430*, we observed a residual expression of IDS. The p.Arg233Gly and p.Glu430* mutants had a residuary enzymatic activity that was lowered by 14.3 and 76-fold, respectively, compared with healthy controls. This observation may help explain the mild disease phenotype in MPS II patients who had these two mutations whereas the p.Ser142Phe and p.Ile360Tyrfs*31 mutations caused the severe disease manifestation.
- Hunter syndrome,
- Mucopolysaccharidosis type II,
- Iduronate-2-sulfatase,
- Mutations,
- Glycosaminoglycans

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References(39)

References

[1]	Alonso-Fernández, J.R., Fidalgo, J., Colón, C. Neonatal screening for mucopolysaccharidoses by determination of glycosaminoglycans in the eluate of urine-impregnated paper: preliminary results of an improved DMB-based procedure J. Clin. Lab. Anal., 24 (2010),pp. 149-153
[2]	Beck, M. Mucopolysaccharidosis type II (Hunter Syndrome): clinical picture and treatment Curr. Pharm. Biotechnol., 12 (2011),pp. 861-866
[3]	Berg, K., Danes, B.S., Bearn, A.G. The linkage relation of the loci for the Xm serum system and the X-linked form of Hurler's syndrome (Hunter's syndrome) Am. J. Hum. Genet., 20 (1968),pp. 398-401
[4]	Braunlin, E.A., Harmatz, H.R., Scarpa, M. et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management J. Inherit. Metab. Dis., 34 (2011),pp. 1183-1197
[5]	Bunge, S., Rathmann, M., Steglich, C. et al. 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 (1998),pp. 492-500
[6]	Chang, J.H., Lin, S.P., Lin, S.C. et al. Expression studies of mutations underlying Taiwanese Hunter syndrome (mucopolysaccharidosis type II) Hum. Genet., 116 (2005),pp. 160-166
[7]	de Jong, J.G., Heijs, W.M., Wevers, R.A. Mucopolysaccharidoses screening: dimethylmethylene blue versus alcian blue Ann. Clin. Biochem., 31 (1994),pp. 267-271
[8]	Filocamo, M., Bonuccelli, G., Corsolini, F. et al. Hum. Mutat., 18 (2001),pp. 164-165
[9]	Froissart, R., Da Silva, I.M., Maire, I. Mucopolysaccharidosis type II: an update on mutation spectrum Acta Paediatr. Suppl., 96 (2007),pp. 71-77
[10]	Froissart, R., Maire, I., Millat, G. et al. Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients Clin. Genet., 53 (1998),pp. 362-368
[11]	Froissart, R., Moreira da Silva, I., Guffon, N. et al. Mucopolysaccharidosis type II ‒ genotype/phenotype aspects Acta Paediatr. Suppl., 91 (2002),pp. 82-87
[12]	Hopwood, J.J., Bunge, S., Morris, C.P. et al. Molecular basis of mucopolysaccharidosis type II: mutations in the iduronate-2-sulphatase gene Hum. Mutat., 2 (1993),pp. 435-442
[13]	Iozzo, R.V. Matrix proteoglycans: from molecular design to cellular function Annu. Rev. Biochem., 67 (1998),pp. 609-652
[14]	Isogai, K., Sukegawa, K., Tomatsu, S. et al. Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease) J. Inherit. Metab. Dis., 21 (1998),pp. 60-70
[15]	Karsten, S., Voskoboeva, E., Krasnopolskaja, X. et al. Hum. Mutat., 14 (1999),pp. 471-476
[16]	Karsten, S., Voskoboeva, E., Tishkanina, S. et al. Hum. Genet., 103 (1998),pp. 732-735
[17]	Keeratichamroen, S., Cairns, J.R., Wattanasirichaigoon, D. et al. Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome J. Inherit. Metab. Dis., 31 (2008),pp. S303-S311
[18]	Kloska, A., Jakóbkiewicz-Banecka, J., Tylki-Szymańska, A. et al. Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders Clin. Genet., 80 (2011),pp. 459-465
[19]	Krabbi, K., Joost, K., Zordania, R. et al. The live-birth prevalence of mucopolysaccharidoses in Estonia Genet. Test. Mol. Biomarkers, 16 (2012),pp. 846-849
[20]	Lampe, C., Bellettato, C.M., Karabul, N. et al. Mucopolysaccharidoses and other lysosomal storage diseases Rheum. Dis. Clin. North Am., 39 (2013),pp. 431-455
[21]	Li, P., Bellows, A.B., Thompson, J.N. Molecular basis of iduronate-2 sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome) J. Med. Genet., 36 (1999),pp. 21-27
[22]	Lin, S.P., Chang, J.H., Lee-Chen, G.J. et al. 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 (2006),pp. 29-34
[23]	Nelson, J., Crowhurst, J., Carey, B. et al. Incidence of the mucopolysaccharidoses in Western Australia Am. J. Med. Genet. A, 123A (2003),pp. 310-313
[24]	Parenti, G., Meroni, G., Ballabio, A. The sulfatase gene family Curr. Opin. Genet. Dev., 7 (1997),pp. 386-391
[25]	Parkinson, E.J., Muller, V., Hopwood, J.J. et al. Iduronate-2-sulphatase protein detection in plasma from mucopolysaccharidosis type II patients Mol. Genet. Metab., 81 (2004),pp. 58-64
[26]	Per, S.R., Abruzzo, J.L., Heimer, R. Analysis of immune complexes by two-dimensional gel electrophoresis Clin. Immunol. Immunopathol., 34 (1985),pp. 165-173
[27]	Sáenz, H., Lareo, L., Poutou, R.A. et al. Computational prediction of the tertiary structure of the human iduronate 2-sulfate sulfatase Biomedica, 27 (2007),pp. 7-20
[28]	Sarrazin, S., Lamanna, W.C., Esko, J.D. Heparan sulfate proteoglycans Cold Spring Harb. Perspect. Biol., 3 (2011)
[29]	Sohn, Y.B., Kim, S.J., Park, S.W. et al. A mother and daughter with the p.R443X mutation of mucopolysaccharidosis type II: genotype and phenotype analysis Am. J. Med. Genet. A, 152A (2010),pp. 3129-3132
[30]	Sosa, A., Barrera, L. Production of specific chicken egg yolk antibodies to iduronate 2-sulphate sulphatase (IDS) and its applicability in an enzime-linked immunosorbent assay (Elisa) J. Inherit. Metab. Dis., 28 (2005),p. 185
[31]	Sukegawa, K., Tomatsu, S., Fukao, T. et al. Mucopolysaccharidosis type II (Hunter disease): identification and characterization of eight point mutations in the iduronate-2-sulfatase gene in Japanese patients Hum. Mutat., 6 (1995),pp. 136-143
[32]	Sukegawa-Kawasaka, K., Kato, Z., Nakamura, H. et al. 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 (2006),pp. 755-761
[33]	Timms, K.M., Lu, F., Shen, Y. et al. 130 kb of DNA sequence reveals two new genes and a regional duplication distal to the human iduronate-2-sulfate sulfatase locus Genome Res., 5 (1995),pp. 71-78
[34]	Vafiadaki, E., Cooper, A., Heptinstall, L.E. et al. Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease) Arch. Dis. Child., 79 (1998),pp. 237-241
[35]	von Bülow, R., Schmidt, B., Dierks, T. et al. Crystal structure of an enzyme-substrate complex provides insight into the interaction between human arylsulfatase A and its substrates during catalysis J. Mol. Biol., 305 (2001),pp. 269-277
[36]	Voznyi, Y.V., Keulemans, J.L., van Diggelen, O.P. A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease) J. Inherit. Metab. Dis., 24 (2001),pp. 675-680
[37]	Wilson, P.J., Suthers, G.K., Callen, D.F. et al. Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome Hum. Genet., 86 (1991),pp. 505-508
[38]	Zhang, H., Li, J., Zhang, X. et al. PLoS ONE, 6 (2011),p. e22951
[39]	Zlotogora, J., Schaap, T., Zeigler, M. et al. Hunter syndrome among Ashkenazi Jews in Israel; evidence for prenatal selection favoring the Hunter allele Hum. Genet., 71 (1985),pp. 329-333