5 results on '"Owen, Liusaidh J."'
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2. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA–protein interaction
- Author
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Williamson, Kathleen A., Hall, H. Nikki, Owen, Liusaidh J., Livesey, Benjamin J., Hanson, Isabel M., Adams, G. G. W., Bodek, Simon, Calvas, Patrick, Castle, Bruce, Clarke, Michael, Deng, Alexander T., Edery, Patrick, Fisher, Richard, Gillessen-Kaesbach, Gabriele, Heon, Elise, Hurst, Jane, Josifova, Dragana, Lorenz, Birgit, McKee, Shane, Meire, Francoise, Moore, Anthony T., Parker, Michael, Reiff, Charlotte M., Self, Jay, Tobias, Edward S., Verheij, Joke B. G. M., Willems, Marjolaine, Williams, Denise, van Heyningen, Veronica, Marsh, Joseph A., and FitzPatrick, David R.
- Published
- 2020
- Full Text
- View/download PDF
3. Characterization of an eye field-like state during optic vesicle organoid development.
- Author
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Owen, Liusaidh J., Rainger, Jacqueline, Bengani, Hemant, Kilanowski, Fiona, FitzPatrick, David R., and Papanastasiou, Andrew S.
- Subjects
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TRANSCRIPTION factors , *GENE expression , *NUCLEOTIDE sequence , *GENE regulatory networks , *GROUP formation - Abstract
Specification of the eye field (EF) within the neural plate marks the earliest detectable stage of eye development. Experimental evidence, primarily from non-mammalian model systems, indicates that the stable formation of this group of cells requires the activation of a set of key transcription factors. This crucial event is challenging to probe in mammals and, quantitatively, little is known regarding the regulation of the transition of cells to this ocular fate. Using optic vesicle organoids to model the onset of the EF, we generate timecourse transcriptomic data allowing us to identify dynamic gene expression programmes that characterize this cellular-state transition. Integrating this with chromatin accessibility data suggests a direct role of canonical EF transcription factors in regulating these gene expression changes, and highlights candidate cis-regulatory elements through which these transcription factors act. Finally, we begin to test a subset of these candidate enhancer elements, within the organoid system, by perturbing the underlying DNA sequence and measuring transcriptomic changes during EF activation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability.
- Author
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Bengani, Hemant, Grozeva, Detelina, Moyon, Lambert, Bhatia, Shipra, Louros, Susana R., Hope, Jilly, Jackson, Adam, Prendergast, James G., Owen, Liusaidh J., Naville, Magali, Rainger, Jacqueline, Grimes, Graeme, Halachev, Mihail, Murphy, Laura C., Spasic-Boskovic, Olivera, van Heyningen, Veronica, Kind, Peter, Abbott, Catherine M., Osterweil, Emily, and Raymond, F. Lucy
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INTELLECTUAL disabilities ,LABORATORY mice ,X chromosome ,EXOMES ,PHENOTYPES ,NUCLEOTIDE sequencing ,OLFACTORY receptors - Abstract
Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1
CRE and TENM1CRE , showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
5. Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability
- Author
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Catherine M. Abbott, Mihail Halachev, Detelina Grozeva, Hugues Roest Crollius, F. Lucy Raymond, James Prendergast, Peter C. Kind, Hemant Bengani, Jacqueline K. Rainger, Laura C. Murphy, Liusaidh J Owen, Veronica van Heyningen, Adam Jackson, Lambert Moyon, Graeme R. Grimes, Olivera Spasic-Boskovic, Magali Naville, Emily K. Osterweil, Jilly Hope, David R. FitzPatrick, Shipra Bhatia, Susana R. Louros, MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, University of Cambridge [UK] (CAM), Cardiff University, Cambridge University Hospitals NHS Foundation Trust, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Grozeva, Detelina [0000-0003-3239-8415], Moyon, Lambert [0000-0003-2390-3942], Bhatia, Shipra [0000-0002-2091-7858], Louros, Susana R. [0000-0002-1012-0386], Jackson, Adam [0000-0002-3554-6682], Prendergast, James G. [0000-0001-8916-018X], Owen, Liusaidh J. [0000-0003-0363-1775], Naville, Magali [0000-0002-6821-2427], Grimes, Graeme [0000-0002-3106-5996], Halachev, Mihail [0000-0002-4594-4588], Murphy, Laura C. [0000-0003-0029-0434], Spasic-Boskovic, Olivera [0000-0003-1583-8132], van Heyningen, Veronica [0000-0003-0359-0141], Abbott, Catherine M. [0000-0001-8794-7173], Osterweil, Emily [0000-0003-0582-2284], FitzPatrick, David R. [0000-0003-4861-969X], Apollo - University of Cambridge Repository, Louros, Susana R [0000-0002-1012-0386], Prendergast, James G [0000-0001-8916-018X], Owen, Liusaidh J [0000-0003-0363-1775], Murphy, Laura C [0000-0003-0029-0434], Abbott, Catherine M [0000-0001-8794-7173], and FitzPatrick, David R [0000-0003-4861-969X]
- Subjects
Male ,Embryology ,Embryo, Nonmammalian ,X-linked intellectual disability ,medicine.disease_cause ,Hippocampus ,Midbrain ,Animals, Genetically Modified ,Cohort Studies ,Fragile X Mental Retardation Protein ,Mice ,0302 clinical medicine ,Gene Frequency ,Genes, X-Linked ,Medicine and Health Sciences ,Exome ,Regulatory Elements, Transcriptional ,Zebrafish ,X chromosome ,Genetics ,0303 health sciences ,education.field_of_study ,Mutation ,Mammalian Genomics ,Multidisciplinary ,Eukaryota ,Brain ,Chromosome Mapping ,Tenascin ,Animal Models ,Genomics ,Pedigree ,Phenotype ,Experimental Organism Systems ,Osteichthyes ,Vertebrates ,Medicine ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Anatomy ,Brainstem ,Research Article ,Genotype ,Science ,Population ,Mouse Models ,Nerve Tissue Proteins ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,medicine ,Animals ,Humans ,Allele ,education ,Gene ,Alleles ,030304 developmental biology ,Whole genome sequencing ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Genome, Human ,Embryos ,Organisms ,Biology and Life Sciences ,medicine.disease ,FMR1 ,Disease Models, Animal ,Fish ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Animal Genomics ,Genetic Loci ,Animal Studies ,Mental Retardation, X-Linked ,Zoology ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Funder: BBSRC studentship, Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
- Published
- 2021
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