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Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation. / Grodecká, L; Kováčová, T; Kramárek, M; Seneca, S; Stouffs, K; De Laet, C; Majer, F; Kršjaková, T; Hujová, P; Hrnčířová, K; Souček, P; Lissens, W; Buratti, E; Freiberger, Tomas.

In: Journal of Molecular Medicine, Vol. 95, No. 3, 03.2017, p. 299-309.

Research output: Contribution to journalArticle

Harvard

Grodecká, L, Kováčová, T, Kramárek, M, Seneca, S, Stouffs, K, De Laet, C, Majer, F, Kršjaková, T, Hujová, P, Hrnčířová, K, Souček, P, Lissens, W, Buratti, E & Freiberger, T 2017, 'Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation', Journal of Molecular Medicine, vol. 95, no. 3, pp. 299-309. https://doi.org/10.1007/s00109-016-1484-2

APA

Grodecká, L., Kováčová, T., Kramárek, M., Seneca, S., Stouffs, K., De Laet, C., ... Freiberger, T. (2017). Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation. Journal of Molecular Medicine, 95(3), 299-309. https://doi.org/10.1007/s00109-016-1484-2

Vancouver

Author

Grodecká, L ; Kováčová, T ; Kramárek, M ; Seneca, S ; Stouffs, K ; De Laet, C ; Majer, F ; Kršjaková, T ; Hujová, P ; Hrnčířová, K ; Souček, P ; Lissens, W ; Buratti, E ; Freiberger, Tomas. / Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation. In: Journal of Molecular Medicine. 2017 ; Vol. 95, No. 3. pp. 299-309.

BibTeX

@article{d7059567859149fba7833fffbd6b51e5,
title = "Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation",
abstract = "Abstract: Mutations affecting splicing underlie the development of many human genetic diseases, but rather rarely through mechanisms of pseudoexon activation. Here, we describe a novel c.1092T>A mutation in the iduronate-2-sulfatase (IDS) gene detected in a patient with significantly decreased IDS activity and a clinical diagnosis of mild mucopolysaccharidosis II form. The mutation created an exonic de novo acceptor splice site and resulted in a complex splicing pattern with multiple pseudoexon activation in the patient’s fibroblasts. Using an extensive series of minigene splicing experiments, we showed that the competition itself between the de novo and authentic splice site led to the bypass of the authentic one. This event then resulted in activation of several cryptic acceptor and donor sites in the upstream intron. As this was an unexpected and previously unreported mechanism of aberrant pseudoexon inclusion, we systematically analysed and disproved that the patient’s mutation induced any relevant change in surrounding splicing regulatory elements. Interestingly, all pseudoexons included in the mature transcripts overlapped with the IDS alternative terminal exon 7b suggesting that this sequence represents a key element in the IDS pre-mRNA architecture. These findings extend the spectrum of mechanisms enabling pseudoexon activation and underscore the complexity of mutation-induced splicing aberrations. Key message: Novel exonic IDS gene mutation leads to a complex splicing pattern.Mutation activates multiple pseudoexons through a previously unreported mechanism.Multiple cryptic splice site (ss) activation results from a bypass of authentic ss.Authentic ss bypass is due to a competition between de novo and authentic ss.",
keywords = "Adolescent, Exons, Glycoproteins/genetics, Humans, Introns, Male, Mucopolysaccharidosis II/genetics, Mutation, Point Mutation, RNA Splice Sites, RNA Splicing, RNA, Messenger/genetics",
author = "L Grodeck{\'a} and T Kov{\'a}čov{\'a} and M Kram{\'a}rek and S Seneca and K Stouffs and {De Laet}, C and F Majer and T Kršjakov{\'a} and P Hujov{\'a} and K Hrnč{\'i}řov{\'a} and P Souček and W Lissens and E Buratti and Tomas Freiberger",
year = "2017",
month = "3",
doi = "10.1007/s00109-016-1484-2",
language = "English",
volume = "95",
pages = "299--309",
journal = "Journal of Molecular Medicine",
issn = "0946-2716",
publisher = "Springer Verlag",
number = "3",

}

RIS

TY - JOUR

T1 - Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation

AU - Grodecká, L

AU - Kováčová, T

AU - Kramárek, M

AU - Seneca, S

AU - Stouffs, K

AU - De Laet, C

AU - Majer, F

AU - Kršjaková, T

AU - Hujová, P

AU - Hrnčířová, K

AU - Souček, P

AU - Lissens, W

AU - Buratti, E

AU - Freiberger, Tomas

PY - 2017/3

Y1 - 2017/3

N2 - Abstract: Mutations affecting splicing underlie the development of many human genetic diseases, but rather rarely through mechanisms of pseudoexon activation. Here, we describe a novel c.1092T>A mutation in the iduronate-2-sulfatase (IDS) gene detected in a patient with significantly decreased IDS activity and a clinical diagnosis of mild mucopolysaccharidosis II form. The mutation created an exonic de novo acceptor splice site and resulted in a complex splicing pattern with multiple pseudoexon activation in the patient’s fibroblasts. Using an extensive series of minigene splicing experiments, we showed that the competition itself between the de novo and authentic splice site led to the bypass of the authentic one. This event then resulted in activation of several cryptic acceptor and donor sites in the upstream intron. As this was an unexpected and previously unreported mechanism of aberrant pseudoexon inclusion, we systematically analysed and disproved that the patient’s mutation induced any relevant change in surrounding splicing regulatory elements. Interestingly, all pseudoexons included in the mature transcripts overlapped with the IDS alternative terminal exon 7b suggesting that this sequence represents a key element in the IDS pre-mRNA architecture. These findings extend the spectrum of mechanisms enabling pseudoexon activation and underscore the complexity of mutation-induced splicing aberrations. Key message: Novel exonic IDS gene mutation leads to a complex splicing pattern.Mutation activates multiple pseudoexons through a previously unreported mechanism.Multiple cryptic splice site (ss) activation results from a bypass of authentic ss.Authentic ss bypass is due to a competition between de novo and authentic ss.

AB - Abstract: Mutations affecting splicing underlie the development of many human genetic diseases, but rather rarely through mechanisms of pseudoexon activation. Here, we describe a novel c.1092T>A mutation in the iduronate-2-sulfatase (IDS) gene detected in a patient with significantly decreased IDS activity and a clinical diagnosis of mild mucopolysaccharidosis II form. The mutation created an exonic de novo acceptor splice site and resulted in a complex splicing pattern with multiple pseudoexon activation in the patient’s fibroblasts. Using an extensive series of minigene splicing experiments, we showed that the competition itself between the de novo and authentic splice site led to the bypass of the authentic one. This event then resulted in activation of several cryptic acceptor and donor sites in the upstream intron. As this was an unexpected and previously unreported mechanism of aberrant pseudoexon inclusion, we systematically analysed and disproved that the patient’s mutation induced any relevant change in surrounding splicing regulatory elements. Interestingly, all pseudoexons included in the mature transcripts overlapped with the IDS alternative terminal exon 7b suggesting that this sequence represents a key element in the IDS pre-mRNA architecture. These findings extend the spectrum of mechanisms enabling pseudoexon activation and underscore the complexity of mutation-induced splicing aberrations. Key message: Novel exonic IDS gene mutation leads to a complex splicing pattern.Mutation activates multiple pseudoexons through a previously unreported mechanism.Multiple cryptic splice site (ss) activation results from a bypass of authentic ss.Authentic ss bypass is due to a competition between de novo and authentic ss.

KW - Adolescent

KW - Exons

KW - Glycoproteins/genetics

KW - Humans

KW - Introns

KW - Male

KW - Mucopolysaccharidosis II/genetics

KW - Mutation

KW - Point Mutation

KW - RNA Splice Sites

KW - RNA Splicing

KW - RNA, Messenger/genetics

UR - http://www.scopus.com/inward/record.url?scp=84994700888&partnerID=8YFLogxK

U2 - 10.1007/s00109-016-1484-2

DO - 10.1007/s00109-016-1484-2

M3 - Article

C2 - 27837218

VL - 95

SP - 299

EP - 309

JO - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

SN - 0946-2716

IS - 3

ER -

ID: 27522890