title: Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene.
abstract: Metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA), is inherited as an autosomal recessive trait, and its frequency is estimated to be 1 in 40,000 live births. Genomic DNA from 21 MLD patients (14 late-infantile and 7 juvenile cases) was amplified in four overlapping PCR fragments and tested by allele-specific oligonucleotide (ASO) for the two common mutations 459 + 1G-->A and P426L. These mutations were found in only 28.6% of the alleles studied. The remaining alleles were analyzed by chemical mismatch cleavage (CMC) and automatic sequencing. In addition to five previously reported mutations (459 + 1G-->A, A212V, R244C, R390W, P426L), 10 novel mutations were identified: 9 missense mutations (S95N, G119R, D152Y, R244H, S250Y, A314T, R384C, R496H, K367N) and one 8 bp deletion in exon 1, the first mutation reported in this exon. These methods allowed us to identify 76% of the alleles tested. Genotype-phenotype correlations could be established for some of these mutations. These results confirm the heterogeneity of mutations causing MLD and suggest that CMC is a reliable and informative screening method for point mutation detection in the arylsulfatase A gene.
authors.affiliation: Genetics Laboratory, René Descartes University (Paris V) CHU Cochin-Port Royal, U129 INSERM, France.
authors.forename: R
authors.initials: R
authors.lastname: Draghia
authors.forename: F
authors.initials: F
authors.lastname: Letourneur
authors.forename: C
authors.initials: C
authors.lastname: Drugan
authors.forename: J
authors.initials: J
authors.lastname: Manicom
authors.forename: C
authors.initials: C
authors.lastname: Blanchot
authors.forename: A
authors.initials: A
authors.lastname: Kahn
authors.forename: L
authors.initials: L
authors.lastname: Poenaru
authors.forename: C
authors.initials: C
authors.lastname: Caillaud
mesh_terms: D000483:Alleles; D002553:Cerebroside-Sulfatase / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005838:Genotype; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000235:genetics*; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D002553:Cerebroside-Sulfatase