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Updated: Mar 3, 2026

Removal of an Internal Translational Start Site from mRNA While Retaining Expression of the Full-Length Protein
Published on: March 16, 2022
Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease
Wen-Hsin Chang1, Dau-Ming Niu2,3, Chi-Yu Lu4,5
1Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
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.
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