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

Human MutationVolume 14, Issue 3 p. 240-248 Research Article 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 Laura Gort, Laura Gort Institut de Bioquímica Clínica, Barcelona, SpainSearch for more papers by this authorM. Josep Coll, M. Josep Coll Institut de Bioquímica Clínica, Barcelona, SpainSearch for more papers by this authorAmparo Chabás, Corresponding Author Amparo Chabás [email protected] medicina.ub.es Institut de Bioquímica Clínica, Barcelona, SpainInstitut de Bioquímica Clínica, C/ Mejía Lequerica s/n, Edifici Helios III, 08028 Barcelona, Spain; Fax: 34-93-227-5668Search for more papers by this author Laura Gort, Laura Gort Institut de Bioquímica Clínica, Barcelona, SpainSearch for more papers by this authorM. Josep Coll, M. Josep Coll Institut de Bioquímica Clínica, Barcelona, SpainSearch for more papers by this authorAmparo Chabás, Corresponding Author Amparo Chabás [email protected] medicina.ub.es Institut de Bioquímica Clínica, Barcelona, SpainInstitut de Bioquímica Clínica, C/ Mejía Lequerica s/n, Edifici Helios III, 08028 Barcelona, Spain; Fax: 34-93-227-5668Search for more papers by this author First published: 02 September 1999 https://doi.org/10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-LCitations: 33AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic leukodystrophy (MLD), a lysosomal disorder with no specific treatment. In view of the importance of genetic counseling, analyses of mutations and polymorphisms, including the ARSA pseudodeficiency allele, were carried out in 18 unrelated Spanish MLD patients. A systematic search allowed us to identify 100% of the alleles involving 17 different mutations, 12 of which are novel: G32S, L68P, R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6-12C→G. Two new polymorphisms, 2033C>T and 2059C>T, were identified in intron 6 which, in combination with two polymorphisms previously described (2161C>G and 2213C>G), gave rise to four different haplotypes in the control population. In addition, we also studied polymorphism 842G>T. Linkage disequilibrium was detected between mutations IVS2+1G→A, D255H, and T327I and specific haplotypes, suggesting a unique origin for these mutations. Moreover, mutation T327I was always associated with the T allele of the new rare variant A210A (893C>T). The distribution of mutation D255H (frequency 19.4%) among patients with different MLD clinical presentation revealed a clear genotype–phenotype correlation paralleling that reported for mutation IVS2+1G→A (frequency 25%). Among the novel mutations, only P136S and R288H occurred on a background of the ARSA pseudodeficiency allele. Screening 182 normal chromosomes identified a frequency of 8.8% of this allele; moreover, we identified two unrelated subjects with the polyA- mutation in the absence of the N350S mutation, and this infrequent haplotype reinforced the heterogeneity of conditions with ARSA deficiency. Hum Mutat 14:240–248, 1999. © 1999 Wiley-Liss, Inc. REFERENCES Barth ML, Fensom A, Harris A. 1993. Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. 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