title: Determination of arylsulfatase A pseudodeficiency allele and haplotype frequency in the Tunisian population.
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.
authors.affiliation: Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Belvédère, Tunisia. benhalim_nizar@yahoo.fr.
authors.forename: Nizar
authors.initials: N
authors.lastname: Ben Halim
authors.affiliation: Child Neurological Diseases Unit, Faculty of Medicine, 1007, Tunis, Tunisia.|INSERM U676, 75935, Paris Cedex 19, France.
authors.forename: Imen
authors.initials: I
authors.lastname: Dorboz
authors.affiliation: Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Belvédère, Tunisia.
authors.forename: Rym
authors.initials: R
authors.lastname: Kefi
authors.affiliation: Bioinformatics Unit, Centre of Biotechnology of Sfax, 3018, Sfax, Tunisia.
authors.forename: Najla
authors.initials: N
authors.lastname: Kharrat
authors.affiliation: Faculté de Médecine, INSERM UMR 931, GReD, 63000, Clermont-Ferrand, France.|Department of Genetics and Cytogenetics, CHU de Clermont-Ferrand, 63003, Clermont-Ferrand Cedax 1, France.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Eymard-Pierre
authors.affiliation: Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Belvédère, Tunisia.
authors.forename: Majdi
authors.initials: M
authors.lastname: Nagara
authors.affiliation: Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Belvédère, Tunisia.
authors.forename: Lilia
authors.initials: L
authors.lastname: Romdhane
authors.affiliation: Laboratory of Epidemiology, Institut Pasteur de Tunis, 1002, Tunis, Tunisia.
authors.forename: Nissaf
authors.initials: N
authors.lastname: Ben Alaya-Bouafif
authors.affiliation: Bioinformatics Unit, Centre of Biotechnology of Sfax, 3018, Sfax, Tunisia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Rebai
authors.affiliation: Child Neurological Diseases Unit, Faculty of Medicine, 1007, Tunis, Tunisia.
authors.forename: Najoua
authors.initials: N
authors.lastname: Miladi
authors.affiliation: INSERM U676, 75935, Paris Cedex 19, France.|Assistance Publique des Hôpitaux de Paris (APHP), Centre de Reference « leucodystrophies », Hôpital Robert Debré, 75019, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, 75205, Paris Cedex 13, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.affiliation: Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Belvédère, Tunisia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Abdelhak
mesh_terms: D000328:Adult; D000483:Alleles; D044383:Black People / Q000235:genetics; D002553:Cerebroside-Sulfatase / Q000172:deficiency* / Q000235:genetics*; D005787:Gene Frequency; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009154:Mutation; D011110:Polymorphism, Genetic; D015995:Prevalence; D025341:Principal Component Analysis; D014416:Tunisia / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D002553:Cerebroside-Sulfatase
keywords: Arylsulfatase A pseudo-deficiency; Genetic differentiation; Genetic polymorphism; Haplotype analysis; Linkage disequilibrium; Tunisia