Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants
Abstract
Background: Pre-mRNA splicing is a complex process requiring the identification of donor site, acceptor site, and branch point site with an adjacent polypyrimidine tract sequence. Splicing is regulated by splicing regulatory elements (SREs) with both enhancer and suppressor functions. Variants located in exonic regions can impact splicing through dysregulation of native splice sites, SREs, and cryptic splice site activation. While splicing dysregulation is considered primary disease-inducing mechanism of synonymous variants, its contribution toward disease phenotype of non-synonymous variants is underappreciated. Methods: In this study, we analyzed 415 disease-causing and 120 neutral F9 exonic point variants including both synonymous and non-synonymous for their effect on splicing using a series of in silico splice site prediction tools, SRE prediction tools, and in vitro minigene assays. Results: The use of splice site and SRE prediction tools in tandem provided better prediction but were not always in agreement with the minigene assays. The net effect of splicing dysregulation caused by variants was context dependent. Minigene assays revealed that perturbed splicing can be found. Conclusion: Synonymous variants primarily cause disease phenotype via splicing dysregulation while additional mechanisms such as translation rate also play an important role. Splicing dysregulation is likely to contribute to the diseasemore »
- Authors:
-
[1]
- Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation &, Research US FDA Silver Spring Maryland
- Department of Statistics University of Connecticut Storrs Connecticut
- Department of Biological, Geological and Environmental Sciences, Center for Gene Regulation in Health and Disease Cleveland State University Cleveland Ohio
- Publication Date:
- Research Org.:
- Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE; US Food and Drug Administration
- OSTI Identifier:
- 1559339
- Alternate Identifier(s):
- OSTI ID: 1559340; OSTI ID: 1623575
- Grant/Contract Number:
- SC0014664
- Resource Type:
- Published Article
- Journal Name:
- Molecular Genetics & Genomic Medicine
- Additional Journal Information:
- Journal Name: Molecular Genetics & Genomic Medicine Journal Volume: 7 Journal Issue: 8; Journal ID: ISSN 2324-9269
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Genetics & Heredity; hemophilia B; in silico splicing analysis; in vitro minigene assay; splicing dysregulation; synonymous variants
Citation Formats
Katneni, Upendra K., Liss, Aaron, Holcomb, David, Katagiri, Nobuko H., Hunt, Ryan, Bar, Haim, Ismail, Amra, Komar, Anton A., and Kimchi‐Sarfaty, Chava. Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants. United States: N. p., 2019.
Web. doi:10.1002/mgg3.840.
Katneni, Upendra K., Liss, Aaron, Holcomb, David, Katagiri, Nobuko H., Hunt, Ryan, Bar, Haim, Ismail, Amra, Komar, Anton A., & Kimchi‐Sarfaty, Chava. Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants. United States. https://doi.org/10.1002/mgg3.840
Katneni, Upendra K., Liss, Aaron, Holcomb, David, Katagiri, Nobuko H., Hunt, Ryan, Bar, Haim, Ismail, Amra, Komar, Anton A., and Kimchi‐Sarfaty, Chava. Sun .
"Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants". United States. https://doi.org/10.1002/mgg3.840.
@article{osti_1559339,
title = {Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants},
author = {Katneni, Upendra K. and Liss, Aaron and Holcomb, David and Katagiri, Nobuko H. and Hunt, Ryan and Bar, Haim and Ismail, Amra and Komar, Anton A. and Kimchi‐Sarfaty, Chava},
abstractNote = {Background: Pre-mRNA splicing is a complex process requiring the identification of donor site, acceptor site, and branch point site with an adjacent polypyrimidine tract sequence. Splicing is regulated by splicing regulatory elements (SREs) with both enhancer and suppressor functions. Variants located in exonic regions can impact splicing through dysregulation of native splice sites, SREs, and cryptic splice site activation. While splicing dysregulation is considered primary disease-inducing mechanism of synonymous variants, its contribution toward disease phenotype of non-synonymous variants is underappreciated. Methods: In this study, we analyzed 415 disease-causing and 120 neutral F9 exonic point variants including both synonymous and non-synonymous for their effect on splicing using a series of in silico splice site prediction tools, SRE prediction tools, and in vitro minigene assays. Results: The use of splice site and SRE prediction tools in tandem provided better prediction but were not always in agreement with the minigene assays. The net effect of splicing dysregulation caused by variants was context dependent. Minigene assays revealed that perturbed splicing can be found. Conclusion: Synonymous variants primarily cause disease phenotype via splicing dysregulation while additional mechanisms such as translation rate also play an important role. Splicing dysregulation is likely to contribute to the disease phenotype of several non=synonymous variants.},
doi = {10.1002/mgg3.840},
journal = {Molecular Genetics & Genomic Medicine},
number = 8,
volume = 7,
place = {United States},
year = {2019},
month = {6}
}
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Figures / Tables:
TABLE 1: Exonic distribution of F9 disease‐causing and neutral variants analyzed in the study
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