Evidence map›Paper›PMID 39084224›Full record

ArticleAmerican journal of human genetics2024

RNA variant assessment using transactivation and transdifferentiation.

Emmylou C Nicolas-Martinez, Olivia Robinson, Christian Pflueger, Alison Gardner, Mark A Corbett, Tarin Ritchie, Thessa Kroes, Clare L van Eyk, Ingrid E Scheffer, Michael S Hildebrand and 23 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

33 authors.

Emmylou C Nicolas-MartinezThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia.
Olivia RobinsonThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia.
Christian PfluegerHarry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
Alison GardnerThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Mark A CorbettThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
Tarin RitchieThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Thessa KroesThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
Clare L van EykThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
Ingrid E SchefferEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Michael S HildebrandEpilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia; The Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia.
Jean-Vianney BarnierInstitut des Neurosciences Paris-Saclay, UMR 9197, CNRS, Université Paris-Saclay, Saclay, France.
Véronique RousseauInstitut des Neurosciences Paris-Saclay, UMR 9197, CNRS, Université Paris-Saclay, Saclay, France.
David GenevieveMontpellier University, Inserm U1183, Reference Center for Rare Diseases Developmental Anomaly and Malformative Syndromes, Genetics Department, Montpellier Hospital, Montpellier, France.
Virginie HaushalterGenetic Diagnosis Laboratory, Strasbourg University Hospital, Strasbourg, France.
Amélie PitonGenetic Diagnosis Laboratory, Strasbourg University Hospital, Strasbourg, France.
Anne-Sophie Denommé-PichonCRMRs "Anomalies du Développement et syndromes malformatifs" et "Déficiences Intellectuelles de causes rares", Centre de Génétique, CHU Dijon, Dijon, France; INSERM UMR1231, GAD "Génétique des Anomalies du Développement," FHU-TRANSLAD, University of Burgundy, Dijon, France.
Ange-Line BruelCRMRs "Anomalies du Développement et syndromes malformatifs" et "Déficiences Intellectuelles de causes rares", Centre de Génétique, CHU Dijon, Dijon, France; INSERM UMR1231, GAD "Génétique des Anomalies du Développement," FHU-TRANSLAD, University of Burgundy, Dijon, France.
Sophie NambotCRMRs "Anomalies du Développement et syndromes malformatifs" et "Déficiences Intellectuelles de causes rares", Centre de Génétique, CHU Dijon, Dijon, France; INSERM UMR1231, GAD "Génétique des Anomalies du Développement," FHU-TRANSLAD, University of Burgundy, Dijon, France.
Bertrand IsidorCRMRs "Anomalies du Développement et syndromes malformatifs" et "Déficiences Intellectuelles de causes rares", Centre de Génétique, CHU Dijon, Dijon, France; INSERM UMR1231, GAD "Génétique des Anomalies du Développement," FHU-TRANSLAD, University of Burgundy, Dijon, France.
John GriggSpeciality of Ophthalmology, Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2000, Australia.
Tina GonzalezDepartment of Clinical Genetics, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Sondhya GhediaDepartment of Clinical Genetics, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
Rhett G MarchantKids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2000, Australia.
Adam BournazosKids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Children's Medical Research Institute, Westmead, NSW 2145, Australia.
Wui-Kwan WongKids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Children's Medical Research Institute, Westmead, NSW 2145, Australia; Department of Paediatric Neurology, Children's Hospital at Westmead, Sydney, NSW 2000, Australia.
Richard I WebsterDepartment of Paediatric Neurology, Children's Hospital at Westmead, Sydney, NSW 2000, Australia.
Frances J EvessonKids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2000, Australia; Children's Medical Research Institute, Westmead, NSW 2145, Australia.
Kristi J JonesKids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Children's Medical Research Institute, Westmead, NSW 2145, Australia; Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, NSW 2000, Australia.
PERSYST Investigator Team
Sandra T CooperKids Neuroscience Centre, Kids Research, Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2000, Australia; Children's Medical Research Institute, Westmead, NSW 2145, Australia.
Ryan ListerHarry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
Jozef GeczThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address: jozef.gecz@adelaide.edu.au.
Lachlan A JollyThe Robinson Research Institute, University of Adelaide, Adelaide, SA 5005, Australia; School of Biomedicine, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: lachlan.jolly@adelaide.edu.au.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Understanding the impact of splicing and nonsense variants on RNA is crucial for the resolution of variant classification as well as their suitability for precision medicine interventions. This is primarily enabled through RNA studies involving transcriptomics followed by targeted assays using RNA isolated from clinically accessible tissues (CATs) such as blood or skin of affected individuals. Insufficient disease gene expression in CATs does however pose a major barrier to RNA based investigations, which we show is relevant to 1,436 Mendelian disease genes. We term these "silent" Mendelian genes (SMGs), the largest portion (36%) of which are associated with neurological disorders. We developed two approaches to induce SMG expression in human dermal fibroblasts (HDFs) to overcome this limitation, including CRISPR-activation-based gene transactivation and fibroblast-to-neuron transdifferentiation. Initial transactivation screens involving 40 SMGs stimulated our development of a highly multiplexed transactivation system culminating in the 6- to 90,000-fold induction of expression of 20/20 (100%) SMGs tested in HDFs. Transdifferentiation of HDFs directly to neurons led to expression of 193/516 (37.4%) of SMGs implicated in neurological disease. The magnitude and isoform diversity of SMG expression following either transactivation or transdifferentiation was comparable to clinically relevant tissues. We apply transdifferentiation and/or gene transactivation combined with short- and long-read RNA sequencing to investigate the impact that variants in USH2A, SCN1A, DMD, and PAK3 have on RNA using HDFs derived from affected individuals. Transactivation and transdifferentiation represent rapid, scalable functional genomic solutions to investigate variants impacting SMGs in the patient cell and genomic context.

Indexed as

Cell TransdifferentiationFibroblastsNeuronsTranscriptional ActivationCRISPR-Cas SystemsHumansRNARNA

Identifiers

PMID39084224
PMCPMC11339655

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.