Abstract
Arylsulfatase A (ASA) is a lysosomal enzyme involved in the catabolism of cerebroside sulfate. ASA deficiency is associated with metachromatic leukodystrophy (MLD). Low ASA activities have also been reported in a more common condition with no apparent clinical consequences termed ASA pseudo-deficiency (ASA-PD) which is associated with two linked mutations in the ASA gene (c.1049A>G and c.*96A>G). This study aimed to investigate the frequency of the two ASA-PD variants and their linkage disequilibrium (LD) among Tunisians. ASA-PD variants were detected in 129 healthy Tunisians and their frequencies were compared to those described worldwide. The frequency of the PD allele was estimated at 17.4 % for the overall sample, with c.1049A>G and c.*96A>G frequencies of 25.6 and 17.4 %, respectively. This study also revealed a high LD between the two ASA-PD variants (r 2 = 0.61). Inter-population analysis revealed similarities in the ASA-PD genetic structure between Tunisians and populations from Middle East with c.*96A>G frequencies being the highest in the world. A significant North vs. South genetic differentiation in the ASA-PD frequency was also observed in Tunisian population who seems genetically intermediate between Africans, Middle-Easterners and Europeans. This is the first report on the allele frequency of the ASA-PD in North Africa, revealing a relatively high frequency of the PD allele among Tunisians. This study gives also evidence on the importance of discriminating ASA-PD allele from pathological mutations causing MLD and supporting enzymatic activity testing with both sulfatiduria determination and genetic testing in the differential diagnosis of MLD in the Tunisian population.
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References
Kreysing J, von Figura K, Gieselmann V (1990) Structure of the arylsulfatase A gene. Eur J Biochem 191(3):627–631
Kolodny EH, Fluharty AL (1995) Metachromatic leukodystrophy and multiple sulfatase deficiency: sulfatide lipidosis. In: Scriver CR, Beaudet A, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York
Gieselmann V, Polten A, Kreysing J, von Figura K (1989) Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site. Proc Natl Acad Sci USA 86(23):9436–9440
Barth ML, Ward C, Harris A, Saad A, Fensom A (1994) Frequency of arylsulphatase A pseudodeficiency associated mutations in a healthy population. J Med Genet 31(9):667–671
Pedron CG, Gaspar PA, Giugliani R, Pereira ML (1999) Arylsulfatase A pseudodeficiency in healthy Brazilian individuals. Braz J Med Biol Res 32(8):941–945 pii:S0100-879X(99)03200802
Cui Y, Colsch B, Afonso C, Baumann N, Tabet JC, Mallet JM, Zhang Y (2008) Synthetic sulfogalactosylceramide (sulfatide) and its use for the mass spectrometric quantitative urinary determination in metachromatic leukodystrophies. Glycoconj J 25(2):147–155. doi:10.1007/s10719-007-9067-7
Whitfield PD, Sharp PC, Johnson DW, Nelson P, Meikle PJ (2001) Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry. Mol Genet Metab 73(1):30–37. doi:10.1006/mgme.2001.3165
Ott R, Waye JS, Chang PL (1997) Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency. Hum Genet 101(2):135–140
Ricketts MH, Goldman D, Long JC, Manowitz P (1996) Arylsulfatase A pseudodeficiency-associated mutations: population studies and identification of a novel haplotype. Am J Med Genet 67(4):387–392. doi:10.1002/(SICI)1096-8628(19960726)67:4<387:AID-AJMG12>3.0.CO;2-F
Zlotogora J, Furman-Shaharabani Y, Goldenfum S, Winchester B, von Figura K, Gieselmann V (1994) Arylsulfatase A pseudodeficiency: a common polymorphism which is associated with a unique haplotype. Am J Med Genet 52(2):146–150. doi:10.1002/ajmg.1320520205
Weir BS (1996) Data analysis II. Sinauer Associates, Sunderland
Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989. doi:10.1086/319501
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296(5576):2225–2229. doi:10.1126/science.1069424
Sangiorgi S, Ferlini A, Zanetti A, Mochi M (1991) Reduced activity of arylsulfatase A and predisposition to neurological disorders: analysis of 140 pediatric patients. Am J Med Genet 40(3):365–369. doi:10.1002/ajmg.1320400324
Tinuper P, Plazzi G, Monari L, Sangiorgi S, Pellissier JF, Cerullo A, Provini F, Capellari S, Baruzzi A, Lugaresi E et al (1994) Arylsulfatase A pseudodeficiency and Lafora bodies in a patient with progressive myoclonic epilepsy. Epilepsia 35(2):332–335
Marcao A, Pinto E, Rocha S, Sa Miranda MC, Ferreira L, Amaral O (2003) ARSA-PD associated alleles in the Portuguese population: frequency determination and haplotype analysis. Mol Genet Metab 79(4):305–307 pii:S1096719203000921
Philpot M, Lewis K, Pereria ML, Ward C, Holmes C, Lovestone S, Fensom A, Seller M (1997) Arylsulphatase A pseudodeficiency in vascular dementia and Alzheimer’s disease. Neuroreport 8(11):2613–2616
Ameur A (1960) La Tunisie à travers l’histoire (Arab version)
Athanasiadis G, Esteban E, Via M, Dugoujon JM, Moschonas N, Chaabani H, Moral P (2007) The X chromosome Alu insertions as a tool for human population genetics: data from European and African human groups. Eur J Hum Genet 15(5):578–583. doi:10.1038/sj.ejhg.5201797
Athanasiadis G, Gonzalez-Perez E, Esteban E, Dugoujon JM, Stoneking M, Moral P (2010) The Mediterranean Sea as a barrier to gene flow: evidence from variation in and around the F7 and F12 genomic regions. BMC Evol Biol 10:84. doi:10.1186/1471-2148-10-84
Fadhlaoui-Zid K, Plaza S, Calafell F, Ben Amor M, Comas D, Bennamar El gaaied A (2004) Mitochondrial DNA heterogeneity in Tunisian Berbers. Ann Hum Genet 68(Pt 3):222–233. doi:10.1046/j.1529-8817.2004.00096.x
Abun-Nasr JM (1987) A history of the Maghrib in the Islamic period. Cambridge University Press, Cambridge
Bognar SK, Furac I, Kubat M, Cosovic C, Demarin V (2002) Croatian population data for arylsulfatase a pseudodeficiency-associated mutations in healthy subjects, and in patients with Alzheimer-type dementia and Down syndrome. Arch Med Res 33(5):473–477 pii:S0188-4409(02)00392-2
Chabas A, Castellvi S, Bayes M, Balcells S, Grinberg D, Vilageliu L, Marfany G, Lissens W, Gonzalez-Duarte R (1993) Frequency of the arylsulphatase A pseudodeficiency allele in the Spanish population. Clin Genet 44(6):320–323
Czartoryska B, Zimowski JG, Bisko M, Gorska D (1996) Arylsulfatase A pseudodeficiency—incidence in Poland. Eur J Hum Genet 4(5):301–303
Hwu WL, Tsai LP, Wang WC, Chuang SC, Wang PJ, Wang TR (1996) Arylsulfatase A pseudodeficiency in Chinese. Hum Genet 97(2):148–149
Nelson PV, Carey WF, Morris CP (1991) Population frequency of the arylsulphatase A pseudo-deficiency allele. Hum Genet 87(1):87–88
Gort L, Coll MJ, Chabas A (1999) Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients. Hum Mutat 14(3):240–248. doi:10.1002/(SICI)1098-1004(1999)14:3<240:AID-HUMU7>3.0.CO;2-L
Leistner S, Young E, Meaney C, Winchester B (1995) Pseudodeficiency of arylsulphatase A: strategy for clarification of genotype in families of subjects with low ASA activity and neurological symptoms. J Inherit Metab Dis 18(6):710–716
Julien CA (1994) Histoire de l’Afrique du Nord: des origines à 1830. Payot
Acknowledgments
The authors are grateful to all volunteers who kindly accepted to be enrolled in this study. The authors would also like to thank Meherzia Ben Fadhel, Sonia Chakroun and Sihem Ben Fadhel for their help in collecting material and for their skilful technical assistance.
This work was supported by the Ministry of Higher Education and Scientific Research and by the Ministry of Health.
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Ben Halim, N., Dorboz, I., Kefi, R. et al. Determination of arylsulfatase A pseudodeficiency allele and haplotype frequency in the Tunisian population. Neurol Sci 37, 403–409 (2016). https://doi.org/10.1007/s10072-015-2417-5
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DOI: https://doi.org/10.1007/s10072-015-2417-5