Modulation the alternative splicing of GLA (IVS4+919G %26gt; A) in Fabry disease

作者：Chang Wen Hsin; Niu Dau Ming; Lu Chi Yu; Lin Shyr Yi; Liu Ta Chih; Chang Jan Gowth

来源：PLos One, 2017, 12(4): e0175929.

DOI：10.1371/journal.pone.0175929

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.

• 出版日期2017-4-21
• 单位中国医科大学