Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria

2021 ◽  
Vol 512 ◽  
pp. 117-120
Author(s):  
Sun Young Cho ◽  
Eunice Yuen-Ting Lau ◽  
David Chi-Kong Luk ◽  
Chun-Yiu Law ◽  
Chi-Kong Lai ◽  
...  
Keyword(s):  
Aberrant Splicing ◽  
Variegate Porphyria

scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Masahiko Ajiro ◽  
Tomonari Awaya ◽  
Young Jin Kim ◽  
Kei Iida ◽  
Masatsugu Denawa ◽  
...  
Keyword(s):  
Small Molecule ◽  
Genetic Disease ◽  
Therapeutic Strategy ◽  
Therapeutic Potential ◽  
Familial Dysautonomia ◽  
Therapeutic Modality ◽  
Aberrant Splicing ◽  
Intronic Splicing Enhancer ◽  
Exon 20 ◽  
Splicing Enhancer

AbstractApproximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5′ splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases.

scholarly journals Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 130
Author(s):  
Flavia Zita Francies ◽  
Sheynaz Bassa ◽  
Aristotelis Chatziioannou ◽  
Andreas Martin Kaufmann ◽  
Zodwa Dlamini
Keyword(s):  
Cervical Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapy Resistance ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Molecular Alteration ◽  
Common Cancer ◽  
Potential Biomarkers

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

scholarly journals Regulation of RNA Splicing: Aberrant Splicing Regulation and Therapeutic Targets in Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 923
Author(s):  
Koji Kitamura ◽  
Keisuke Nimura
Keyword(s):  
Dna Sequences ◽  
Rna Splicing ◽  
Splicing Factors ◽  
Splicing Regulation ◽  
Aberrant Splicing ◽  
Aberrant Expression ◽  
Non Coding Rnas ◽  
Precursor Mrna ◽  
Splicing Enhancer ◽  
Small Nuclear Ribonucleoproteins

RNA splicing is a critical step in the maturation of precursor mRNA (pre-mRNA) by removing introns and exons. The combination of inclusion and exclusion of introns and exons in pre-mRNA can generate vast diversity in mature mRNA from a limited number of genes. Cancer cells acquire cancer-specific mechanisms through aberrant splicing regulation to acquire resistance to treatment and to promote malignancy. Splicing regulation involves many factors, such as proteins, non-coding RNAs, and DNA sequences at many steps. Thus, the dysregulation of splicing is caused by many factors, including mutations in RNA splicing factors, aberrant expression levels of RNA splicing factors, small nuclear ribonucleoproteins biogenesis, mutations in snRNA, or genomic sequences that are involved in the regulation of splicing, such as 5’ and 3’ splice sites, branch point site, splicing enhancer/silencer, and changes in the chromatin status that affect the splicing profile. This review focuses on the dysregulation of RNA splicing related to cancer and the associated therapeutic methods.

Powdery mildew resistance in the Japanese domestic tobacco cultivar Kokubu is associated with aberrant splicing ofMLOorthologues

2016 ◽  
Vol 65 (8) ◽  
pp. 1358-1365 ◽  
Author(s):  
T. Fujimura ◽  
S. Sato ◽  
T. Tajima ◽  
M. Arai
Keyword(s):  
Powdery Mildew ◽  
Powdery Mildew Resistance ◽  
Aberrant Splicing ◽  
Mildew Resistance ◽  
Tobacco Cultivar

scholarly journals Aberrant Splicing in Transgenes Containing Introns, Exons, and V5 Epitopes: Lessons from Developing an FSHD Mouse Model Expressing a D4Z4 Repeat with Flanking Genomic Sequences

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0118813 ◽  
Author(s):  
Eugénie Ansseau ◽  
Jacqueline S. Domire ◽  
Lindsay M. Wallace ◽  
Jocelyn O. Eidahl ◽  
Susan M. Guckes ◽  
...  
Keyword(s):  
Mouse Model ◽  
Genomic Sequences ◽  
Aberrant Splicing ◽  
D4z4 Repeat

A novel mutation in thePLCD1gene, which leads to an aberrant splicing event, underlies autosomal recessive leuconychia

2012 ◽  
Vol 167 (4) ◽  
pp. 946-949 ◽  
Author(s):  
M. Farooq ◽  
M. Kurban ◽  
O. Abbas ◽  
O. Obeidat ◽  
H. Fujikawa ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Novel Mutation ◽  
Aberrant Splicing

scholarly journals Metals accelerate production of the aberrant splicing isoform of the presenilin-2

2004 ◽  
Vol 88 (6) ◽  
pp. 1345-1351 ◽  
Author(s):  
Shinsuke Matsuzaki ◽  
Takayuki Manabe ◽  
Taiichi Katayama ◽  
Atsuko Nishikawa ◽  
Takeshi Yanagita ◽  
...  
Keyword(s):  
Aberrant Splicing ◽  
Presenilin 2
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