Abstract
Background
Mucopolysaccharidoses type III (MPS III) are a group of autosomal recessive lysosomal storage diseases, caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate: heparan sulfate sulfamidase (SGSH), α-Nacetylglucosaminidase (NAGLU), heparan sulfate acetyl-CoA: α-glucosaminide N-acetyltransferase (HGSNAT), and N-acetylglucosamine-6-sulfatase (GNS).
Methods
In this study, we have performed the molecular analysis of the SGSH, NAGLU and HGSNAT genes in 10 patients from 6 different MPS III Tunisian families.
Results
In the SGSH gene, two mutations were identified: one novel (p.D477N) and one already described (p.Q365X). In the NAGLU gene, two novel mutations were discovered (p.L550P and p.E153X). For the novel missense mutations found in these two genes we performed an in silico structural analysis and the results were consistent with the clinical course of the patients harboring those mutations. Finally, in HGSNAT gene, we found the splicesite mutation c.234+1G>A that had already been reported as relatively frequent in MPS IIIC patients from countries surrounding the basin of the Mediterranean sea. Its presence in two Tunisian MPS IIIC families points to the hypothesis of its peri Mediterranean origin. With the exception of the c.234+1G>A mutation, that was identified in two unrelated MPS IIIC families, the other identified mutations were family-specific and were always found in homozygosity in the patients studied, thus reflecting the existence of consanguinity in MPS III Tunisian families.
Conclusions
Three novel mutations are reported here, further contributing to the knowledge of the molecular basis of these diseases. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to an improvement in genetic counseling.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGrawHill, 2001: 3421–3453.
Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: diagnostic, clinical, and biological implications. Hum Mutat 2001;18:264–281.
Feldhammer M, Durand S, Mrázová L, Boucher RM, Laframboise R, Steinfeld R, et al. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alphaglucosaminide N-acetyltransferase (HGSNAT) gene. Hum Mutat 2009;30:918–925.
Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochem Res Int 2012;2012:471325.
Scott HS, Blanch L, Guo XH, Freeman C, Orsborn A, Baker E, et al. Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome. Nat Genet 1995;11:465–467.
Zhao HG, Li HH, Bach G, Schmidtchen A, Neufeld EF. The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci USA 1996;93:6101–6105.
Fan X, Zhang H, Zhang S, Bagshaw RD, Tropak MB, Callahan JW, et al. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C). Am J Hum Genet 2006;79:738–744.
Hrebícek M, Mrázová L, Seyrantepe V, Durand S, Roslin NM, Nosková L, et al. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Am J Hum Genet 2006;79:807–819.
Mok A, Cao H, Hegele RA. Genomicbasis of mucopolysaccharidosis type IIID (MIM 252940) revealed by sequencing of GNS encoding N-acetylglucosamine-6-sulfatase. Genomics 2003;81:1–5.
Ouesleti S, Brunel V, Ben Turkia H, Dranguet H, Miled A, Miladi N, et al. Molecular characterization of MPS IIIA, MPS IIIB and MPS IIIC in Tunisian patients. Clin Chim Acta 2011;412:2326–2331.
Ben Halim N, Ben Alaya Bouafif N, Romdhane L, Kefi Ben Atig R, Chouchane I, Bouyacoub Y, et al. Consanguinity, endogamy, and genetic disorders in Tunisia. J Community Genet 2013;4:273–284.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–249.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073–1081.
Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 2015;31:2745–2747.
Ficko-Blean E, Stubbs KA, Nemirovsky O, Vocadlo DJ, Boraston AB. Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB. Proc Natl Acad Sci USA 2008;105:6560–6565.
Sidhu NS, Schreiber K, Pröpper K, Becker S, Usón I, Sheldrick GM, et al. Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. Acta Crystallogr D Biol Crystallogr 2014;70:1321–1335.
Esposito S, Balzano N, Daniele A, Villani GR, Perkins K, Weber B, et al. Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects. Biochim Biophys Acta 2000;1501:1–11.
Dipple KM, McCabe ER. Modifier genes convert "simple" Mendelian disorders to complex traits. Mol Genet Metab 2000;71:43–50.
Héron B, Mikaeloff Y, Froissart R, Caridade G, Maire I, Caillaud C, et al. Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A 2011;155A:58–68.
Pollard LM, Jones JR, Wood TC. Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. J Inherit Metab Dis 2013;36:179–187.
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;11:313–320.
Weber B, Guo XH, Wraith JE, Cooper A, Kleijer WJ, Bunge S, et al. Novel mutations in Sanfilippo A syndrome: implications for enzyme function. Hum Mol Genet 1997;6:1573–1579.
Schmidtchen A, Greenberg D, Zhao HG, Li HH, Huang Y, Tieu P, et al. NAGLU mutations underlying Sanfilippo syndrome type B. Am J Hum Genet 1998;62:64–69.
Beesley CE, Young EP, Vellodi A, Winchester BG. Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). J Med Genet 1998;35:910–914.
Bunge S, Knigge A, Steglich C, Kleijer WJ, van Diggelen OP, Beck M, et al. Mucopolysaccharidosis type IIIB (Sanfilippo B): identification of 18 novel alpha-N-acetylglucosaminidase gene mutations. J Med Genet 1999;36:28–31.
Weber B, Guo XH, 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. Eur J Hum Genet 1999;7:34–44.
Feldhammer M, Durand S, Mrázová L, Boucher RM, Laframboise R, Steinfeld R, et al. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alphaglucosaminide N-acetyltransferase (HGSNAT) gene. Hum Mutat 2009;30:918–925.
Canals I, Elalaoui SC, Pineda M, Delgadillo V, Szlago M, Jaouad IC, et al. Molecular analysis of Sanfilippo syndrome type C in Spain: seven novel HGSNAT mutations and characterization of the mutant alleles. Clin Genet 2011;80:367–374.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ouesleti, S., Coutinho, M.F., Ribeiro, I. et al. Update of the spectrum of mucopolysaccharidoses type III in Tunisia: identification of three novel mutations and in silico structural analysis of the missense mutations. World J Pediatr 13, 374–380 (2017). https://doi.org/10.1007/s12519-017-0005-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12519-017-0005-x