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Metachromatic leukodystrophy: Identification of the first deletion in exon 1 and nine novel point mutations in the arylsulfatase A gene
Author(s) -
Draghia Ruxandra,
Letourneur Franck,
Drugan Cristina,
Manicom Jeanne,
Blanchot Christophe,
Kahn Axel,
Poenaru Livia,
Caillaud Catherine
Publication year - 1997
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1997)9:3<234::aid-humu4>3.0.co;2-7
Subject(s) - metachromatic leukodystrophy , arylsulfatase a , biology , genetics , point mutation , exon , missense mutation , allele , leukodystrophy , genotype , mutation , arylsulfatase , microbiology and biotechnology , gene , disease , medicine , biochemistry , pathology , enzyme
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. Hum Mutat 9:234–242, 1997. © 1997 Wiley‐Liss, Inc.