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

PLoS One. 2017 Apr 21;12(4):e0175929. doi: 10.1371/journal.pone.0175929. eCollection 2017.

Authors

Wen-Hsin Chang¹, Dau-Ming Niu^{2

3}, Chi-Yu Lu^{4

5}, Shyr-Yi Lin^{1

6}, Ta-Chih Liu^{7

8}, Jan-Gowth Chang^{9

10

11

12}

Affiliations

¹ Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
² Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
³ Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
⁴ Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁶ Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁷ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁹ Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan.
¹⁰ Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan.
¹¹ School of Medicine, China Medical University, Taichung, Taiwan.
¹² Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 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.

MeSH terms

Alternative Splicing*
Amiloride / pharmacology
Exons
Fabry Disease / genetics*
Histones / genetics
Humans
Introns
RNA, Messenger / genetics
alpha-Galactosidase / genetics*

Substances

Histones
RNA, Messenger
Amiloride
alpha-Galactosidase

Grants and funding

This study was supported by grants from the Ministry of Science and Technology, Taiwan (103-2320-B-039-050-MY3), Jin-lung-yuan Foundation, 2015 to 2016 (SYL), China Medical University Hospital (DMR-106-104), and Taipei Veterans General Hospital (VGHUST102-G7-4-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.