Disease modelling of core pre-mRNA splicing factor haploinsufficiencyCitation formats

  • External authors:
  • Katherine Wood
  • Charlie F. Rowland
  • Wasay Mohiuddin Shaikh Qureshi
  • Huw Thomas
  • Weronika Buczek

Standard

Disease modelling of core pre-mRNA splicing factor haploinsufficiency. / Wood, Katherine; Rowland, Charlie F. ; Shaikh Qureshi, Wasay Mohiuddin; Thomas, Huw; Buczek, Weronika; Briggs, Tracy; Hubbard, Simon; Hentges, Kathryn; Newman, William; O'Keefe, Raymond.

In: Genome Medicine, 13.07.2019.

Research output: Contribution to journalArticle

Harvard

APA

Wood, K., Rowland, C. F., Shaikh Qureshi, W. M., Thomas, H., Buczek, W., Briggs, T., ... O'Keefe, R. (2019). Disease modelling of core pre-mRNA splicing factor haploinsufficiency. Genome Medicine. https://doi.org/10.1093/hmg/ddz169

Vancouver

Wood K, Rowland CF, Shaikh Qureshi WM, Thomas H, Buczek W, Briggs T et al. Disease modelling of core pre-mRNA splicing factor haploinsufficiency. Genome Medicine. 2019 Jul 13. https://doi.org/10.1093/hmg/ddz169

Author

Wood, Katherine ; Rowland, Charlie F. ; Shaikh Qureshi, Wasay Mohiuddin ; Thomas, Huw ; Buczek, Weronika ; Briggs, Tracy ; Hubbard, Simon ; Hentges, Kathryn ; Newman, William ; O'Keefe, Raymond. / Disease modelling of core pre-mRNA splicing factor haploinsufficiency. In: Genome Medicine. 2019.

Bibtex

@article{1fc24e5e9cfd4ca0b92d56e879d9a942,
title = "Disease modelling of core pre-mRNA splicing factor haploinsufficiency",
abstract = "The craniofacial disorder Mandibulofacial Dysostosis Guion-Almedia type is caused by haploinsufficiency of the U5 snRNP gene EFTUD2/SNU114. However, it is unclear how reduced expression of this core pre-mRNA splicing factor leads to craniofacial defects. Here we use a CRISPR-Cas9 nickase strategy to generate a human EFTUD2-knockdown cell line, and show that reduced expression of EFTUD2 leads to diminished proliferative ability of these cells, increased sensitivity to endoplasmic reticulum (ER) stress and the mis-expression of several genes involved in the ER stress response. RNA-Seq analysis of the EFTUD2- knockdown cell line revealed transcriptome-wide changes in gene expression, with an enrichment for genes associated with processes involved in craniofacial development. Additionally, our RNA-Seq data identified widespread mis-splicing in EFTUD2-knockdown cells. Analysis of the functional and physical characteristics of mis-spliced pre-mRNAs highlighted conserved properties, including length and splice site strengths, of retained introns and skipped exons in our disease model. We also identified enriched processes associated with the affected genes, including cell death, cell and organ morphology and embryonic development. Together, these data support a model in which EFTUD2 haploinsufficiency leads to the mis-splicing of a distinct subset of pre-mRNAs with a widespread effect on gene expression, including altering the expression of ER stress response genes and genes involved in the development of the craniofacial region. The increased burden of unfolded proteins in the ER resulting from mis-splicing would exceed the capacity of the defective ER stress response, inducing apoptosis in cranial neural crest cells that would result in craniofacial abnormalities during development.",
author = "Katherine Wood and Rowland, {Charlie F.} and {Shaikh Qureshi}, {Wasay Mohiuddin} and Huw Thomas and Weronika Buczek and Tracy Briggs and Simon Hubbard and Kathryn Hentges and William Newman and Raymond O'Keefe",
year = "2019",
month = "7",
day = "13",
doi = "10.1093/hmg/ddz169",
language = "English",
journal = "Genome Medicine",

}

RIS

TY - JOUR

T1 - Disease modelling of core pre-mRNA splicing factor haploinsufficiency

AU - Wood, Katherine

AU - Rowland, Charlie F.

AU - Shaikh Qureshi, Wasay Mohiuddin

AU - Thomas, Huw

AU - Buczek, Weronika

AU - Briggs, Tracy

AU - Hubbard, Simon

AU - Hentges, Kathryn

AU - Newman, William

AU - O'Keefe, Raymond

PY - 2019/7/13

Y1 - 2019/7/13

N2 - The craniofacial disorder Mandibulofacial Dysostosis Guion-Almedia type is caused by haploinsufficiency of the U5 snRNP gene EFTUD2/SNU114. However, it is unclear how reduced expression of this core pre-mRNA splicing factor leads to craniofacial defects. Here we use a CRISPR-Cas9 nickase strategy to generate a human EFTUD2-knockdown cell line, and show that reduced expression of EFTUD2 leads to diminished proliferative ability of these cells, increased sensitivity to endoplasmic reticulum (ER) stress and the mis-expression of several genes involved in the ER stress response. RNA-Seq analysis of the EFTUD2- knockdown cell line revealed transcriptome-wide changes in gene expression, with an enrichment for genes associated with processes involved in craniofacial development. Additionally, our RNA-Seq data identified widespread mis-splicing in EFTUD2-knockdown cells. Analysis of the functional and physical characteristics of mis-spliced pre-mRNAs highlighted conserved properties, including length and splice site strengths, of retained introns and skipped exons in our disease model. We also identified enriched processes associated with the affected genes, including cell death, cell and organ morphology and embryonic development. Together, these data support a model in which EFTUD2 haploinsufficiency leads to the mis-splicing of a distinct subset of pre-mRNAs with a widespread effect on gene expression, including altering the expression of ER stress response genes and genes involved in the development of the craniofacial region. The increased burden of unfolded proteins in the ER resulting from mis-splicing would exceed the capacity of the defective ER stress response, inducing apoptosis in cranial neural crest cells that would result in craniofacial abnormalities during development.

AB - The craniofacial disorder Mandibulofacial Dysostosis Guion-Almedia type is caused by haploinsufficiency of the U5 snRNP gene EFTUD2/SNU114. However, it is unclear how reduced expression of this core pre-mRNA splicing factor leads to craniofacial defects. Here we use a CRISPR-Cas9 nickase strategy to generate a human EFTUD2-knockdown cell line, and show that reduced expression of EFTUD2 leads to diminished proliferative ability of these cells, increased sensitivity to endoplasmic reticulum (ER) stress and the mis-expression of several genes involved in the ER stress response. RNA-Seq analysis of the EFTUD2- knockdown cell line revealed transcriptome-wide changes in gene expression, with an enrichment for genes associated with processes involved in craniofacial development. Additionally, our RNA-Seq data identified widespread mis-splicing in EFTUD2-knockdown cells. Analysis of the functional and physical characteristics of mis-spliced pre-mRNAs highlighted conserved properties, including length and splice site strengths, of retained introns and skipped exons in our disease model. We also identified enriched processes associated with the affected genes, including cell death, cell and organ morphology and embryonic development. Together, these data support a model in which EFTUD2 haploinsufficiency leads to the mis-splicing of a distinct subset of pre-mRNAs with a widespread effect on gene expression, including altering the expression of ER stress response genes and genes involved in the development of the craniofacial region. The increased burden of unfolded proteins in the ER resulting from mis-splicing would exceed the capacity of the defective ER stress response, inducing apoptosis in cranial neural crest cells that would result in craniofacial abnormalities during development.

U2 - 10.1093/hmg/ddz169

DO - 10.1093/hmg/ddz169

M3 - Article

JO - Genome Medicine

JF - Genome Medicine

ER -