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

J 2017

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

GRODECKÁ, Lucie; Tatiana KOVÁČOVÁ; Michal KRAMÁREK; S. SENECA; K. STOUFFS et al.

Základní údaje

Originální název

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

Autoři

Vydání

JOURNAL OF MOLECULAR MEDICINE-JMM, NEW YORK, SPRINGER, 2017, 0946-2716

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30101 Human genetics

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.938

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/17:00095653

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

Complex splicing aberration; Splice site competition; Pseudoexon; De novo splice site; IDS

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 28. 2. 2018 16:29, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

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.

Návaznosti

MUNI/A/1183/2015, interní kód MU

Název: Patogeneze a léčba humorální imunodeficiencí

Investor: Masarykova univerzita, Patogeneze a léčba humorální imunodeficiencí, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

NV16-34414A, projekt VaV

Název: Určení genových oblastí náchylných ke vzniku mutací ovlivňujících sestřih mRNA

Citovat

GRODECKÁ, Lucie; Tatiana KOVÁČOVÁ; Michal KRAMÁREK; S. SENECA; K. STOUFFS; C. DE LAET; F. MAJER; Tereza KRŠJAKOVÁ; Pavla HUJOVÁ; Kristýna HRNČÍŘOVÁ; Přemysl SOUČEK; W. LISSENS; E. BURATTI a Tomáš FREIBERGER. Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation. JOURNAL OF MOLECULAR MEDICINE-JMM. NEW YORK: SPRINGER, 2017, roč. 95, č. 3, s. 299-309. ISSN 0946-2716. Dostupné z: https://doi.org/10.1007/s00109-016-1484-2.

@article{1387537,
   author = {Grodecká, Lucie and Kováčová, Tatiana and Kramárek, Michal and Seneca, S. and Stouffs, K. and De Laet, C. and Majer, F. and Kršjaková, Tereza and Hujová, Pavla and Hrnčířová, Kristýna and Souček, Přemysl and Lissens, W. and Buratti, E. and Freiberger, Tomáš},
   article_location = {NEW YORK},
   article_number = {3},
   doi = {https://doi.org/10.1007/s00109-016-1484-2},
   keywords = {Complex splicing aberration; Splice site competition; Pseudoexon; De novo splice site; IDS},
   language = {eng},
   issn = {0946-2716},
   journal = {JOURNAL OF MOLECULAR MEDICINE-JMM},
   title = {Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation},
   url = {https://link.springer.com/article/10.1007%2Fs00109-016-1484-2},
   volume = {95},
   year = {2017}
}

TY  - JOUR
ID  - 1387537
AU  - Grodecká, Lucie - Kováčová, Tatiana - Kramárek, Michal - Seneca, S. - Stouffs, K. - De Laet, C. - Majer, F. - Kršjaková, Tereza - Hujová, Pavla - Hrnčířová, Kristýna - Souček, Přemysl - Lissens, W. - Buratti, E. - Freiberger, Tomáš
PY  - 2017
TI  - Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation
JF  - JOURNAL OF MOLECULAR MEDICINE-JMM
VL  - 95
IS  - 3
SP  - 299-309
EP  - 299-309
PB  - SPRINGER
SN  - 09462716
KW  - Complex splicing aberration
KW  - Splice site competition
KW  - Pseudoexon
KW  - De novo splice site
KW  - IDS
UR  - https://link.springer.com/article/10.1007%2Fs00109-016-1484-2
L2  - https://link.springer.com/article/10.1007%2Fs00109-016-1484-2
N2  - 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.
ER  -

GRODECKÁ, Lucie; Tatiana KOVÁČOVÁ; Michal KRAMÁREK; S. SENECA; K. STOUFFS; C. DE LAET; F. MAJER; Tereza KRŠJAKOVÁ; Pavla HUJOVÁ; Kristýna HRNČÍŘOVÁ; Přemysl SOUČEK; W. LISSENS; E. BURATTI a Tomáš FREIBERGER. Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation. \textit{JOURNAL OF MOLECULAR MEDICINE-JMM}. NEW YORK: SPRINGER, 2017, roč.~95, č.~3, s.~299-309. ISSN~0946-2716. Dostupné z: https://doi.org/10.1007/s00109-016-1484-2.

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