Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by mutations in the arylsulfatase A (ASA) gene. We identified a Thai boy with typical late-infantile MLD and found that he was a compound heterozygote for a novel mutation, g.IVS3-2A>G causing c.679-696del inherited from his father, and a previously reported missense mutation, g.1144G>A causing c.1102-1204del inherited from his mother. The g.1144G>A mutation was located in the middle of exon 7 and previously assumed to be deleterious by causing an amino acid change, E382K. We, herein, found that its actual pathogenic effect was splicing-related by disrupting a potential exonic splicing enhancer (ESE) and causing a complete exon 7 skipping. This is the first missense mutation in the ASA gene that is deleterious from disrupting a potential ESE. The results prompted us to investigate pathogenic effects of other reported missense mutations in the ASA gene. Unlike pathogenic missense mutations in some other genes, those in the ASA gene do not colocalize with ESE sites suggesting that pathogenic effects of majority of them are not splicing-related.

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