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

Chang, Wen Hsin; Niu, Dau Ming; Lu, Cheng-Hsien; Lin, Shyr Yi; Liu, Ta Chih; Chang, Jui‐Hsing

doi:10.1371/journal.pone.0175929

Cited by 15 publications

(20 citation statements)

References 42 publications

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“…Specific histone marks can affect the splicing outcome by recruiting splicing factors to the site of transcription (Podlaha et al ., ; Zhou et al ., ). Moreover, we have demonstrated that amiloride reversed aberrant histone modification patterns, resulting in the disruption of the association of splicing complex with the transcripts (Chang et al ., ). To investigate whether histone‐tail PTMs are involved in the BS008‐regulated splicing, we analyzed the effects of BS008 on histone‐tail PTMs in Huh‐7 cells.…”

Section: Resultsmentioning

confidence: 97%

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Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Lee

Chang

et al. 2019

Molecular Oncology

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Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3 , SMAC , and BCL‐X , at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine‐rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF , ATM , AIFM1 , NFKB1 , and API5 , was also modulated by BS008. In vivo experiments further indicated that treatment of tumor‐bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro , either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

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Section: Resultsmentioning

confidence: 97%

“…Taken together, these results suggested that PP1 phosphatase rather than AKT kinase was associated with the dephosphorylation of SRSF3, which in turn played a role in the BS008‐modified AS process. In this regard, BS008 appears similar to amiloride, which regulates the AS through a PP1‐mediated splicing mechanism (Chang et al ., ,, ).…”

Section: Resultsmentioning

confidence: 99%

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Lee

Chang

et al. 2019

Molecular Oncology

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“…NONO also additionally interacts with the C‐terminal of RNA pol IIa and IIo . In some conditions, NONO can also interact with 3′ end of mRNA splicing such as TNF‐a, the exonuclease XRN2, the snRNP‐free U1A and GLA (α‐galactosidase A) …”

Section: Nono and Gene Regulationmentioning

confidence: 99%

NONO and tumorigenesis: More than splicing

Feng

Deng

et al. 2020

J Cellular Molecular Medi

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The NONO (non-POU domain-containing octamer-binding protein) protein, also known as 54 kD nuclear RNA-and DNA-binding protein (p54nrb), belongs to the multifunctional DBHS (Drosophila behaviour/human splicing) family of proteins which can bind DNA, RNA and protein. 1 NONO has a nuclear localization signal (NLS) at its C-terminal, so it is located in the nucleus of most mammalian cells and is primarily distributed in the subnuclear domain named paraspeckles. 2 Emerging evidence strongly indicates new roles for NONO in tumorigenesis, including but not limited to regulating proliferation, apoptosis, cell migration and DNA damage repair. Here, we provide a comprehensive review of the NONO and its functions in tumorigenesis. AbstractThe non-POU domain-containing octamer-binding protein NONO/p54 nrb , which belongs to the Drosophila behaviour/human splicing (DBHS) family, is a multifunctional nuclear protein rarely functioning alone. Emerging solid evidences showed that NONO engages in almost every step of gene regulation, including but not limited to mRNA splicing, DNA unwinding, transcriptional regulation, nuclear retention of defective RNA and DNA repair. NONO is involved in many biological processes including cell proliferation, apoptosis, migration and DNA damage repair. Dysregulation of NONO has been found in many types of cancer. In this review, we summarize the current and fast-growing knowledge about the regulation of NONO, its biological function and implications in tumorigenesis and cancer progression. Overall, significant findings about the roles of NONO have been made, which might make NONO to be a new biomarker or/and a possible therapeutic target for cancers. K E Y W O R D S DBHS, NONO, splicing, tumorigenesis | 4369 FENG Et al.

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“…Through medical and technological development, enzyme replacement therapy (ERT) and chaperone therapy are now available [ [5] , [6] , [7] ], and neonatal and high-risk screening is performed for early diagnosis and early treatment of Fabry patients [ [8] , [9] , [10] , [11] , [12] , [13] ]. Accordingly, an effort to elucidate the characteristics of Fabry patients in various countries and areas has been made [ [11] , [12] , [13] , [14] , [15] , [16] ]. For example, in Japan, many case reports and results of small cohort studies have been published [ [17] , [18] , [19] , [20] ].…”

Section: Introductionmentioning

confidence: 99%

Fabry disease in a Japanese population-molecular and biochemical characteristics

Sakuraba

Tsukimura

Togawa

et al. 2018

Molecular Genetics and Metabolism Reports

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We had experienced 117 Japanese Fabry patients (72 males and 45 females) from 1977 to 2006, and then we generated an improved Fabry analysis system in 2007 and have found 196 ones (95 males and 101 females) since then. In this study, we summarized the data of the patients and tried to elucidate the molecular and biochemical characteristics of Japanese Fabry patients. Gene analysis revealed various GLA mutations, including missense mutations (56.5%, 48 types); nonsense mutations (15.9%, 13 types); deletions (12.6%, 13 types); splicing defects (10.1%, 6 types); insertions (1.0%, 2 types), and insertions/deletions (0.5%, 1 type), in the patients that were tested. Amino acid substitutions resulting from the missense mutations found in the classic form patients tended to be localized in the core of the GLA protein, and those in the later-onset ones in the peripheral region. The most commonly identified pathogenic mutations are c.888G > A (p.M296I), c.936 + 919G > A, c.679C > T (p.R227X), c.335G > A (p.R112H), c.334C > T (p.R112C), and c.902G > A (p.R301Q). Among them, c.888G > A (p.M296I) is unique to Japanese Fabry patients. On the other hand, c.936 + 919G > A is a variant that has been frequently detected in Taiwan Chinese Fabry patients, and c.335G > A (p.R112H) in various countries. These are found in later-onset patients, and c.679C > T (p.R227X) and c.334C > T (p.R112C) classic ones. c.902G > A (p.R301Q) is found in both classic and later-onset form patients. A possible functional polymorphism, c.196G > C (p.E66Q), was identified in 0.4% of the subjects who underwent high-risk screening. The biochemical findings including leukocyte α-galactosidase A activity, plasma globotriaosylsphingosine level and urinary globotriaosylceramide in the individual phenotypic groups well reflected the phenotypic differences in this disease. The results will be useful for understanding the basis of Fabry disease in Japan.

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

Cited by 15 publications

References 42 publications

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

NONO and tumorigenesis: More than splicing

Fabry disease in a Japanese population-molecular and biochemical characteristics

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