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Abstract
While a base substitution in intron 4 of GLA (IVS4+919G>A) that causes aberrant alternative splicing resulting in Fabry disease has been reported, its molecular mechanism remains unclear. Here we reported that upon IVS4+919G>A transversion, H3K36me3 was enriched across the alternatively spliced region. PSIP1, an adapter of H3K36me3, together with Hsp70 and NONO were recruited and formed a complex with SF2/ASF and SRp20, which further promoted GLA splicing. Amiloride, a splicing regulator in cancer cells, could reverse aberrant histone modification patterns and disrupt the association of splicing complex with GLA. It could also reverse aberrant GLA splicing in a PP1-dependant manner. Our findings revealed the alternative splicing mechanism of GLA (IVS4+919G>A), and a potential treatment for this specific genetic type of Fabry disease by amiloride in the future.
Highlights
Fabry disease (FD) is an X-linked lysosomal disorder caused by a deficiency of α galactosidase A (GLA), due to mutations in the GLA gene at Xq22
In order to realize the mechanism of one base transversion leading to the cryptic exon creation, Epstein-Barr virus-transformed lymphoblast cell lines from Fabry disease (FD) patient and health person were established
Because histone acetylation has been correlated with transcriptional activation and alternative splicing changes [16,17,18,19,20,21,22], we suggested that histone acetylation on GLA intron 4 might be involved in transcriptional activation rather than pre-mRNA splicing regulation
Summary
Fabry disease (FD) is an X-linked lysosomal disorder caused by a deficiency of α galactosidase A (GLA), due to mutations in the GLA gene at Xq22. Among the genotype mutations of the GLA gene, the intronic mutation at nucleotide 9331 (IVS4+919G>A) is reported to be a cardiac variant Fabry mutation [4,5,6]. This intronic mutation induces an alternative splicing event in intron 4, which results in an insertion of 57-nt between the exon 4 and 5 of the GLA transcript, generating a premature stop codon.
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