Pseudoexon activation in disease by non-splice site deep intronic sequence variation - wild type pseudoexons constitute high-risk sites in the human genome

doi:10.1002/humu.24306

Review

. 2022 Feb;43(2):103-127.

doi: 10.1002/humu.24306. Epub 2021 Dec 5.

Pseudoexon activation in disease by non-splice site deep intronic sequence variation - wild type pseudoexons constitute high-risk sites in the human genome

Ulrika S S Petersen¹, Thomas K Doktor¹, Brage S Andresen¹

Affiliations

PMID: 34837434
DOI: 10.1002/humu.24306

Review

Pseudoexon activation in disease by non-splice site deep intronic sequence variation - wild type pseudoexons constitute high-risk sites in the human genome

Ulrika S S Petersen et al. Hum Mutat. 2022 Feb.

. 2022 Feb;43(2):103-127.

doi: 10.1002/humu.24306. Epub 2021 Dec 5.

Authors

Ulrika S S Petersen¹, Thomas K Doktor¹, Brage S Andresen¹

Affiliation

¹ Department of Biochemistry and Molecular Biology and the Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense M, Denmark.

PMID: 34837434
DOI: 10.1002/humu.24306

Abstract

Accuracy of pre-messenger RNA (pre-mRNA) splicing is crucial for normal gene expression. Complex regulation supports the spliceosomal distinction between authentic exons and the many seemingly functional splice sites delimiting pseudoexons. Pseudoexons are nonfunctional intronic sequences that can be activated for aberrant inclusion in mRNA, which may cause disease. Pseudoexon activation is very challenging to predict, in particular when activation occurs by sequence variants that alter the splicing regulatory environment without directly affecting splice sites. As pseudoexon inclusion often evades detection due to activation of nonsense-mediated mRNA decay, and because conventional diagnostic procedures miss deep intronic sequence variation, pseudoexon activation is a heavily underreported disease mechanism. Pseudoexon characteristics have mainly been studied based on in silico predicted sequences. Moreover, because recognition of sequence variants that create or strengthen splice sites is possible by comparison with well-established consensus sequences, this type of pseudoexon activation is by far the most frequently reported. Here we review all known human disease-associated pseudoexons that carry functional splice sites and are activated by deep intronic sequence variants located outside splice site sequences. We delineate common characteristics that make this type of wild type pseudoexons distinct high-risk sites in the human genome.

Keywords: RNA sequencing; aberrant splicing; deep intronic sequence variants; human genome; pre-mRNA splicing; pseudoexon.

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References

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1. Amit, M., Donyo, M., Hollander, D., Goren, A., Kim, E., Gelfman, S., Lev-Maor, G., Burstein, D., Schwartz, S., Postolsky, B., Pupko, T., & Ast, G. (2012). Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Reports, 1(5), 543-556. https://doi.org/10.1016/j.celrep.2012.03.013
1. Attig, J., Agostini, F., Gooding, C., Chakrabarti, A. M., Singh, A., Haberman, N., Zagalak, J. A., Emmett, W., Smith, C. W. J., Luscombe, N. M., & Ule, J. (2018). Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing. Cell, 174(5), 1067-1081. https://doi.org/10.1016/j.cell.2018.07.001
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1. Baralle, M., & Baralle, F. E. (2018). The splicing code. Biosystems, 164, 39-48. https://doi.org/10.1016/j.biosystems.2017.11.002

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[1] Albert, S., Garanto, A., Sangermano, R., Khan, M., Bax, N. M., Hoyng, C. B., Zernant, J., Lee, W., Allikmets, R., Collin, R. W. J., & Cremers, F. P. M. (2018). Identification and rescue of splice defects caused by two neighboring deep-intronic ABCA4 mutations underlying Stargardt Disease. The American Journal of Human Genetics, 102(4), 517-527. https://doi.org/10.1016/j.ajhg.2018.02.008

[2] Albert, S., Garanto, A., Sangermano, R., Khan, M., Bax, N. M., Hoyng, C. B., Zernant, J., Lee, W., Allikmets, R., Collin, R. W. J., & Cremers, F. P. M. (2018). Identification and rescue of splice defects caused by two neighboring deep-intronic ABCA4 mutations underlying Stargardt Disease. The American Journal of Human Genetics, 102(4), 517-527. https://doi.org/10.1016/j.ajhg.2018.02.008

[3] Amit, M., Donyo, M., Hollander, D., Goren, A., Kim, E., Gelfman, S., Lev-Maor, G., Burstein, D., Schwartz, S., Postolsky, B., Pupko, T., & Ast, G. (2012). Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Reports, 1(5), 543-556. https://doi.org/10.1016/j.celrep.2012.03.013

[4] Amit, M., Donyo, M., Hollander, D., Goren, A., Kim, E., Gelfman, S., Lev-Maor, G., Burstein, D., Schwartz, S., Postolsky, B., Pupko, T., & Ast, G. (2012). Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Reports, 1(5), 543-556. https://doi.org/10.1016/j.celrep.2012.03.013

[5] Attig, J., Agostini, F., Gooding, C., Chakrabarti, A. M., Singh, A., Haberman, N., Zagalak, J. A., Emmett, W., Smith, C. W. J., Luscombe, N. M., & Ule, J. (2018). Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing. Cell, 174(5), 1067-1081. https://doi.org/10.1016/j.cell.2018.07.001

[6] Attig, J., Agostini, F., Gooding, C., Chakrabarti, A. M., Singh, A., Haberman, N., Zagalak, J. A., Emmett, W., Smith, C. W. J., Luscombe, N. M., & Ule, J. (2018). Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing. Cell, 174(5), 1067-1081. https://doi.org/10.1016/j.cell.2018.07.001

[7] Bampton, A., Gatt, A., Humphrey, J., Cappelli, S., Bhattacharya, D., Foti, S., Brown, A.-L., Asi, Y., Low, Y. H., Foiani, M., Raj, T., Buratti, E., Fratta, P., & Lashley, T. (2021). HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing. Acta Neuropathologica, 142(4), 609-627. https://doi.org/10.1007/S00401-021-02340-0

[8] Bampton, A., Gatt, A., Humphrey, J., Cappelli, S., Bhattacharya, D., Foti, S., Brown, A.-L., Asi, Y., Low, Y. H., Foiani, M., Raj, T., Buratti, E., Fratta, P., & Lashley, T. (2021). HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing. Acta Neuropathologica, 142(4), 609-627. https://doi.org/10.1007/S00401-021-02340-0

[9] Baralle, M., & Baralle, F. E. (2018). The splicing code. Biosystems, 164, 39-48. https://doi.org/10.1016/j.biosystems.2017.11.002

[10] Baralle, M., & Baralle, F. E. (2018). The splicing code. Biosystems, 164, 39-48. https://doi.org/10.1016/j.biosystems.2017.11.002

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Pseudoexon activation in disease by non-splice site deep intronic sequence variation - wild type pseudoexons constitute high-risk sites in the human genome

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Pseudoexon activation in disease by non-splice site deep intronic sequence variation - wild type pseudoexons constitute high-risk sites in the human genome

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