Biopolym. Cell. 2016; 32(5):359-366.
http://dx.doi.org/10.7124/bc.00092D
Molecular Biomedicine
Molecular-genetic characterization of Ukrainian patients with mucopolysaccharidosis IIIA: identification of three new mutations in the heparan-N-sulfatase gene
1, 2Trofimova N. S., 1, 2Olkhovich N. V., 2Gorovenko N. G.
  1. National Children's Specialized Hospital Okhmatdyt, Ministry of Health of Ukraine
    28/1, Chornovola Str., Kyiv, Ukraine, 01135
  2. State Institute of Genetic and Regenerative Medicine, NAMS of Ukraine
    67, Vyshhorodska Str., Kyiv, Ukraine, 04114

Abstract

Mucopolysaccharidosis type III or Sanfilippo syndrome (MIM # 252900) is a rare hereditary autosomal-recessive metabolic disorder, which occurs due to the deficiency of heparan-N-sulfatase enzyme (EC 3.10.1.1). Aim. To identify the whole spectrum of mutations in SGSH gene in Ukrainian patients with MPS III A. Methods. RFLP-analysis, SSCP method, sequencing. Results. We have identified 100 % (42/42) mutant alleles of SGSH gene in 23 patients (two probands had siblings with identical genotypes) with MPS III A from 21 Ukrainian family. The range of mutations in SGSH gene in Ukrainian patients with MPS III A is represented with 7 known missence-mutations , R74C, R245H, T271M, E292K, S298P, E369K, N389K and 2 single nucleotide deletions, c.1080delC and c.1135delG. We identified three new mutations in the SGSH gene: a missence-mutation G149R,a deletion c.216delC, and a deletion of 27 bp TCC^348CTCctgccggcgctggaggccgagcccctcTGGGCCACC. Conclusions. The data obtained may be useful for molecular-genetic analysis of Ukrainian patients with MPS III A.
Keywords: mucopolysaccharidosis, Sanfilippo A syndrome, heparan-N-sulfatase
Full text: (PDF, in English)

References

[1] Bame KJ. Heparanases: endoglycosidases that degrade heparan sulfate proteoglycans. Glycobiology. 2001;11(6):91R-98R.
[2] Scriver CR, Beaudet AL, Sly WS, Valle D. The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, 2001:3421–52.
[3] Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, Kohlschütter A, Kampmann C, Beck M. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28(6):1011-7.
[4] Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet. 1997;101(3):355-8.
[5] Michelakakis H, Dimitriou E, Tsagaraki S, Giouroukos S, Schulpis K, Bartsocas CS. Lysosomal storage diseases in Greece. Genet Couns. 1995;6(1):43-7.
[6] Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, Niezen-Koning KE, van Diggelen OP. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105(1-2):151-6.
[7] Poupetová H, Ledvinová J, Berná L, Dvoráková L, Kozich V, Elleder M. The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations. J Inherit Metab Dis. 2010;33(4):387-96.
[8] Scott HS, Blanch L, Guo XH, Freeman C, Orsborn A, Baker E, Sutherland GR, Morris CP, Hopwood JJ. Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome. Nat Genet. 1995;11(4):465-7.
[9] Karageorgos LE, Guo XH, Blanch L, Weber B, Anson DS, Scott HS, Hopwood JJ. Structure and sequence of the human sulphamidase gene. DNA Res. 1996;3(4):269-71.
[10] Weber B, Guo XH, Wraith JE, Cooper A, Kleijer WJ, Bunge S, Hopwood JJ. Novel mutations in Sanfilippo A syndrome: implications for enzyme function. Hum Mol Genet. 1997;6(9):1573-9.
[11] Bunge S, Ince H, Steglich C, Kleijer WJ, Beck M, Zaremba J, van Diggelen OP, Weber B, Hopwood JJ, Gal A. Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A). Hum Mutat. 1997;10(6):479-85.
[12] Esposito S, Balzano N, Daniele A, Villani GR, Perkins K, Weber B, Hopwood JJ, Di Natale P. Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects. Biochim Biophys Acta. 2000;1501(1):1-11.
[13] Trofimova NS, Olkhovich NV, Gorovenko NG. Specificities of Sanfilippo A syndrome laboratory diagnostics. Biopolym Cell. 2014; 30(5):388-93.
[14] Trofimova NS, Olkhovich NV, Gorovenko NG. [Application of biochemical screening studies in early diagnostics of mucopolysaccharidosis]. Herald of problems of biology and medicine. 2015; 3; 2 (123): 245-50.
[15] Condie A, Eeles R, Borresen AL, Coles C, Cooper C, Prosser J. Detection of point mutations in the p53 gene: comparison of single-strand conformation polymorphism, constant denaturant gel electrophoresis, and hydroxylamine and osmium tetroxide techniques. Hum Mutat. 1993;2(1):58-66.
[16] Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989;86(8):2766-70.
[17] Gilkes JA, Patterson BD, Heldermon CD. Mucopolysaccharidosis III: Molecular genetics and genotype-phenotype correlations. OA Genetics. 2014;2(1):1
[18] Muschol N, Storch S, Ballhausen D, Beesley C, Westermann JC, Gal A, Ullrich K, Hopwood JJ, Winchester B, Braulke T. Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A. Hum Mutat. 2004;23(6):559-66.
[19] Héron B, Mikaeloff Y, Froissart R, Caridade G, Maire I, Caillaud C, Levade T, Chabrol B, Feillet F, Ogier H, Valayannopoulos V, Michelakakis H, Zafeiriou D, Lavery L, Wraith E, Danos O, Heard JM, Tardieu M. Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A. 2011;155A(1):58-68.
[20] Blanch L, Weber B, Guo XH, Scott HS, Hopwood JJ. Molecular defects in Sanfilippo syndrome type A. Hum Mol Genet. 1997;6(5):787-91.
[21] Di Natale P, Balzano N, Esposito S, Villani GR. Identification of molecular defects in Italian Sanfilippo A patients including 13 novel mutations. Hum Mutat. 1998;11(4):313-20.
[22] Piotrowska E, Jakóbkiewicz-Banecka J, Tylki-Szymańska A, Czartoryska B, Wegrzyn A, Wegrzyn G. Correlation between severity of mucopolysaccharidoses and combination of the residual enzyme activity and efficiency of glycosaminoglycan synthesis. Acta Paediatr. 2009;98(4):743-9.
[23] Valstar MJ, Neijs S, Bruggenwirth HT, Olmer R, Ruijter GJ, Wevers RA, van Diggelen OP, Poorthuis BJ, Halley DJ, Wijburg FA. Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations. Ann Neurol. 2010;68(6):876-87.
[24] Meyer A, Kossow K, Gal A, Steglich C, Mühlhausen C, Ullrich K, Braulke T, Muschol N. The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome). Hum Mutat. 2008;29(5):770.