Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease

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

doi:10.1371/journal.pone.0175929

Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease

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

Research output: Contribution to journal › Article › peer-review

12 Citations (Scopus)

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.

Original language	English
Article number	e0175929
Journal	PLoS ONE
Volume	12
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0175929
Publication status	Published - Apr 2017

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title = "Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease",

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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AU - Niu, Dau Ming

AU - Lu, Chi Yu

AU - Lin, Shyr Yi

AU - Liu, Ta Chih

AU - Chang, Jan Gowth

N1 - Publisher Copyright: © 2017 Chang et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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N2 - 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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Modulation the alternative splicing of GLA (IVS4+919G>A) in Fabry disease

Abstract

ASJC Scopus subject areas

UN SDGs

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