{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T20:20:14Z","timestamp":1787602814701,"version":"build-2736575974"},"reference-count":108,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T00:00:00Z","timestamp":1563148800000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["1916606"],"award-info":[{"award-number":["1916606"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["1926882"],"award-info":[{"award-number":["1926882"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/N000358\/1"],"award-info":[{"award-number":["BB\/N000358\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Health Research Manchester Biomedical Research Centre","award":["IS-BRC-1215-20007"],"award-info":[{"award-number":["IS-BRC-1215-20007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The craniofacial disorder mandibulofacial dysostosis Guion-Almeida 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddz169","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T15:10:55Z","timestamp":1562771455000},"page":"3704-3723","source":"Crossref","is-referenced-by-count":27,"title":["Disease modeling of core pre-mRNA splicing factor haploinsufficiency"],"prefix":"10.1093","volume":"28","author":[{"given":"Katherine A","family":"Wood","sequence":"first","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"},{"name":"Center for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, St. Mary\u2019s Hospital, The University of Manchester, Manchester Academic Health Science Centre Manchester, M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie F","family":"Rowlands","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"},{"name":"Center for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, St. Mary\u2019s Hospital, The University of Manchester, Manchester Academic Health Science Centre Manchester, M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wasay Mohiuddin Shaikh","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huw B","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weronika A","family":"Buczek","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy A","family":"Briggs","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"},{"name":"Center for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, St. Mary\u2019s Hospital, The University of Manchester, Manchester Academic Health Science Centre Manchester, M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J","family":"Hubbard","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn E","family":"Hentges","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G","family":"Newman","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"},{"name":"Center for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, St. Mary\u2019s Hospital, The University of Manchester, Manchester Academic Health Science Centre Manchester, M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond T","family":"O\u2019Keefe","sequence":"additional","affiliation":[{"name":"Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,7,13]]},"reference":[{"key":"2019122822374941300_ref1","doi-asserted-by":"crossref","first-page":"a003707","DOI":"10.1101\/cshperspect.a003707","article-title":"Spliceosome structure and function","volume":"3","author":"Will","year":"2011","journal-title":"Cold Spring Harb. 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