Shotelersuk Vorasuk, Desudchit Tayard, Tongkobpetch Siraprapa
Medical Genetics and Metabolism, Department of Pediatrics, Sor Kor Building 11th Floor, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand.
Int J Mol Med. 2004 Oct;14(4):683-9.
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.
异染性脑白质营养不良（MLD）是一种常染色体隐性疾病，由芳基硫酸酯酶A（ASA）基因突变引起。我们鉴定出一名患有典型晚发性婴儿型MLD的泰国男孩，发现他是一个复合杂合子，携带一个从父亲遗传而来的新突变g.IVS3-2A>G，导致c.679-696缺失，以及一个先前报道的错义突变g.1144G>A，导致c.1102-1204缺失，该突变从母亲遗传而来。g.1144G>A突变位于外显子7的中部，先前认为通过导致氨基酸变化E382K而具有有害性。在此，我们发现其实际致病效应与剪接相关，它破坏了一个潜在的外显子剪接增强子（ESE），导致外显子7完全跳跃。这是ASA基因中首个因破坏潜在ESE而具有有害性的错义突变。这些结果促使我们研究ASA基因中其他已报道错义突变的致病效应。与其他一些基因中的致病错义突变不同，ASA基因中的错义突变并不与ESE位点共定位，这表明它们中的大多数致病效应与剪接无关。
