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2. Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus.

Author

Cipriani, Valentina, Silva, Raquel S, Arno, Gavin, Pontikos, Nikolas, Kalhoro, Ambreen, Valeina, Sandra, Inashkina, Inna, Audere, Mareta, Rutka, Katrina, Puech, Bernard, Michaelides, Michel, van Heyningen, Veronica, Lace, Baiba, Webster, Andrew R, and Moore, Anthony T

Subjects
Retina, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Fetus, Humans, Corneal Dystrophies, Hereditary, Homeodomain Proteins, Eye Proteins, Transcription Factors, Tomography, Optical Coherence, Sequence Analysis, DNA, Family, Gene Expression, Base Sequence, Haplotypes, Adult, Female, Male, Genetic Loci, Chromosome Duplication, ADAMTS Proteins, Chromosomes, Human, Pair 5, Pair 6, Corneal Dystrophies, Hereditary, Sequence Analysis, DNA, Tomography, Optical Coherence
Abstract

Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.

Published
2017

3. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author

Arno, Gavin, Carss, Keren J, Hull, Sarah, Zihni, Ceniz, Robson, Anthony G, Fiorentino, Alessia, Hardcastle, Alison J, Holder, Graham E, Cheetham, Michael E, Plagnol, Vincent, Moore, Anthony, Raymond, F Lucy, Matter, Karl, Balda, Maria S, Webster, Andrew R, Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Halford, Stephanie, Yu, Jing, Lise, Stefano, Ponitkos, Nikos, Michaelides, Michel, Webster, Andrew, van Heyningen, Veronica, Aitman, Timothy, Alachkar, Hana, Ali, Sonia, Allen, Louise, Allsup, David, Ambegaonkar, Gautum, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arumugakani, Gururaj, Ashford, Sofie, Astle, William, Attwood, Antony, Austin, Steve, Bacchelli, Chiara, Bakchoul, Tamam, Bariana, Tadbir K, Baxendale, Helen, Bennett, David, Bethune, Claire, Bibi, Shahnaz, Bitner-Glindzicz, Maria, Bleda, Marta, Boggard, Harm, Bolton-Maggs, Paula, Booth, Claire, Bradley, John R, Brady, Angie, Brown, Matthew, Browning, Michael, Bryson, Christine, Burns, Siobhan, Calleja, Paul, Canham, Natalie, Carmichael, Jenny, Carss, Keren, Caulfield, Mark, Chalmers, Elizabeth, Chandra, Anita, Chinnery, Patrick, Chitre, Manali, Church, Colin, Clement, Emma, Clements-Brod, Naomi, Clowes, Virginia, Coghlan, Gerry, Collins, Peter, Cooper, Nichola, Creaser-Myers, Amanda, DaCosta, Rosa, Daugherty, Louise, Davies, Sophie, Davis, John, De Vries, Minka, Deegan, Patrick, Deevi, Sri VV, and Deshpande, Charu

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Human Genome, Rare Diseases, Neurosciences, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, Adult, Alleles, Amino Acid Sequence, Cell Polarity, Epithelial Cells, Exome, Eye Proteins, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Missense, Nerve Tissue Proteins, Pedigree, Phenotype, Retina, Retinal Degeneration, Retinal Dystrophies, Rho Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, UK Inherited Retinal Disease Consortium, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, apicobasal polarity, inherited retinal dystrophy, p114RhoGEF, retinal degeneration, retinitis pigmentosa, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs∗63), c.1996C>T (p.Arg666∗), c.2632G>T (p.Glu878∗), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Published
2017

4. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Author

Arno, Gavin, Agrawal, Smriti A, Eblimit, Aiden, Bellingham, James, Xu, Mingchu, Wang, Feng, Chakarova, Christina, Parfitt, David A, Lane, Amelia, Burgoyne, Thomas, Hull, Sarah, Carss, Keren J, Fiorentino, Alessia, Hayes, Matthew J, Munro, Peter M, Nicols, Ralph, Pontikos, Nikolas, Holder, Graham E, UKIRDC, Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Yu, Jing, Lise, Stefano, Ponitkos, Nikos, Plagnol, Vincent, Michaelides, Michel, Hardcastle, Alison J, Cheetham, Michael E, Webster, Andrew R, van Heyningen, Veronica, Asomugha, Chinwe, Raymond, F Lucy, Moore, Anthony T, Li, Yumei, Cukras, Catherine, and Chen, Rui

Subjects
Genetics, Biotechnology, Neurodegenerative, Rare Diseases, Clinical Research, Eye Disease and Disorders of Vision, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Eye, Adolescent, Alleles, Animals, Child, Child, Preschool, Eye Proteins, Female, Genes, Recessive, Humans, Induced Pluripotent Stem Cells, Male, Membrane Proteins, Membrane Transport Proteins, Mice, Mutation, Mutation, Missense, Phenotype, Photoreceptor Cells, Vertebrate, Retinitis Pigmentosa, Young Adult, UKIRDC, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.

Published
2016

5. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA–protein interaction

Author

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
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6. Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia.

Author

Hall, Hildegard Nikki, Parry, David, Halachev, Mihail, Williamson, Kathleen A., Donnelly, Kevin, Parada, Jose Campos, Bhatia, Shipra, Joseph, Jeffrey, Holden, Simon, Prescott, Trine E., Bitoun, Pierre, Kirk, Edwin P., Newbury-Ecob, Ruth, Lachlan, Katherine, Bernar, Juan, van Heyningen, Veronica, FitzPatrick, David R., and Meynert, Alison

Abstract

Background Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting the PAX6 locus. Methods Short-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in the PAX6 coding region. Results Likely causative mutations were identified in 22 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the PAX6 locus. Of these 19 families, 1 has a novel heterozygous PAX6 frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of PAX6 5' non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions of PAX6, 3 have deletions encompassing critical PAX6 cis-regulatory elements, 2 have balanced inversions with disruptive breakpoints within the PAX6 locus and 2 have complex rearrangements disrupting PAX6. The remaining 3 of 22 families have deletions encompassing FOXC1 (a known cause of atypical aniridia). Seven of the causative variants occurred de novo and one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in PAX6 cis-regulatory elements. Conclusion Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Late-Onset Autosomal Dominant Macular Degeneration Caused by Deletion of the CRX Gene

Author

Yahya, Samar, primary, Smith, Claire E.L., additional, Poulter, James A., additional, McKibbin, Martin, additional, Arno, Gavin, additional, Ellingford, Jamie, additional, Kämpjärvi, Kati, additional, Khan, Muhammad I., additional, Cremers, Frans P.M., additional, Hardcastle, Alison J., additional, Castle, Bruce, additional, Steel, David H.W., additional, Webster, Andrew R., additional, Black, Graeme C., additional, El-Asrag, Mohammed E., additional, Ali, Manir, additional, Toomes, Carmel, additional, Inglehearn, Chris F., additional, Ingram, Stuart, additional, Taylor, Rachel, additional, Manson, Forbes, additional, Sergouniotis, Panagiotis, additional, Pontikos, Nikolas, additional, Cheetham, Michael, additional, Fiorentino, Alessia, additional, Downes, Susan, additional, Yu, Jing, additional, Halford, Stephanie, additional, Broadgate, Suzanne, additional, van Heyningen, Veronica, additional, Ambrose, John C., additional, Arumugam, Prabhu, additional, Bevers, Roel, additional, Bleda, Marta, additional, Boardman-Pretty, Freya, additional, Boustred, Christopher R., additional, Brittain, Helen, additional, Caulfield, Mark J., additional, Chan, Georgia C., additional, Elgar, Greg, additional, Fowler, Tom, additional, Giess, Adam, additional, Hamblin, Angela, additional, Henderson, Shirley, additional, Hubbard, Tim J.P., additional, Jackson, Rob, additional, Jones, Louise J., additional, Kasperaviciute, Dalia, additional, Kayikci, Melis, additional, Kousathanas, Athanasios, additional, Lahnstein, Lea, additional, Leigh, Sarah E.A., additional, Leong, Ivonne U.S., additional, Lopez, Javier F., additional, Maleady-Crowe, Fiona, additional, McEntagart, Meriel, additional, Minneci, Federico, additional, Moutsianas, Loukas, additional, Mueller, Michael, additional, Murugaesu, Nirupa, additional, Need, Anna C., additional, O’Donovan, Peter, additional, Odhams, Chris A., additional, Patch, Christine, additional, Pereira, Mariana Buongermino, additional, Perez-Gil, Daniel, additional, Pullinger, John, additional, Rahim, Tahrima, additional, Rendon, Augusto, additional, Rogers, Tim, additional, Savage, Kevin, additional, Sawant, Kushmita, additional, Scott, Richard H., additional, Siddiq, Afshan, additional, Sieghart, Alexander, additional, Smith, Samuel C., additional, Sosinsky, Alona, additional, Stuckey, Alexander, additional, Tanguy, Mélanie, additional, Taylor Tavares, Ana Lisa, additional, Thomas, Ellen R.A., additional, Thompson, Simon R., additional, Tucci, Arianna, additional, Welland, Matthew J., additional, Williams, Eleanor, additional, Witkowska, Katarzyna, additional, and Wood, Suzanne M., additional

Published
2023
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12. List of Contributors

Author

Abdelalim, Essam M., primary, Agabalyan, Natacha A., additional, Armin, Parth, additional, Bertolini, Jessica, additional, Biernaskie, Jeff, additional, Chambers, Ian, additional, Cheah, Kathryn S.E., additional, Clore, G. Marius, additional, Emara, Mohamed M., additional, Favaro, Rebecca, additional, Hagner, Andrew, additional, Ishii, Yasuo, additional, Jacobs, Ian, additional, Jiang, Ming, additional, Kamachi, Yusuke, additional, Kolatkar, Prasanna R., additional, Kondoh, Hisato, additional, Ku, Wei-Yao, additional, Lovell-Badge, Robin, additional, Mariani, Jessica, additional, Mercurio, Sara, additional, Moovarkumudalvan, Balasubramanian, additional, Muhr, Jonas, additional, Mullin, Nicholas P., additional, Nicolis, Silvia K., additional, Ottolenghi, Sergio, additional, Poot, Raymond A., additional, Prakash, Nilima, additional, Que, Jianwen, additional, Rahmani, Waleed, additional, Rizzoti, Karine, additional, Uchikawa, Masanori, additional, van Heyningen, Veronica, additional, Wong, Frederick C.K., additional, Wong, Neng Chun, additional, and Xu, Pin-Xian, additional

Published
2016
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14. Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability

Author

Bengani, Hemant, primary, Grozeva, Detelina, additional, Moyon, Lambert, additional, Bhatia, Shipra, additional, Louros, Susana R., additional, Hope, Jilly, additional, Jackson, Adam, additional, Prendergast, James G., additional, Owen, Liusaidh J., additional, Naville, Magali, additional, Rainger, Jacqueline, additional, Grimes, Graeme, additional, Halachev, Mihail, additional, Murphy, Laura C., additional, Spasic-Boskovic, Olivera, additional, van Heyningen, Veronica, additional, Kind, Peter, additional, Abbott, Catherine M., additional, Osterweil, Emily, additional, Raymond, F. Lucy, additional, Roest Crollius, Hugues, additional, and FitzPatrick, David R., additional

Published
2021
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15. Functional Predictors of Causative Cis-Regulatory Mutations in Mendelian Disease

Author

Bengani, Hemant, primary, Grozeva, Detelina, additional, Moyon, Lambert, additional, Bhatia, Shipra, additional, Louros, Susana R, additional, Hope, Jilly, additional, Jackson, Adam, additional, Prendergast, James G, additional, Owen, Liusaidh J., additional, Naville, Magali, additional, Rainger, Jacqueline, additional, Grimes, Graeme, additional, Halachev, Mihail, additional, Murphy, Laura C, additional, Spasic-Boskovic, Olivera, additional, van Heyningen, Veronica, additional, Kind, Peter, additional, Abbott, Catherine M, additional, Osterweil, Emily, additional, Raymond, F Lucy, additional, Crollius, Hugues Roest, additional, and FitzPatrick, David R, additional

Published
2020
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16. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA–protein interaction

Author

Williamson, Kathleen K.A., Hall, Hildegard Nikki, Owen, Liusaidh L.J., Livesey, Benjamin B.J., Hanson, Isabel I.M., Adams, Gillian Gwendolen G.G.W., Bodek, Simon, Calvas, Patrick, Castle, Bruce, Clarke, Michael, Deng, Alexander A.T., Edery, Patrick, Fisher, Richard R.S., Gillessen-Kaesbach, Gabriele, Heon, Elise, Hurst, Jane, Josifova, Dragana, Lorenz, Birgit, McKee, Shane, Meire, Françoise, Moore, Anthony Thomas, Parker, Michael W, Reiff, Charlotte C.M., Self, Jay, Tobias, Edward E.S., Verheij, Joke BGM G M J., Willems, Marjolaine, Williams, Denise, Van Heyningen, Veronica, Marsh, Joseph Arthur, FitzPatrick, David D.R., Williamson, Kathleen K.A., Hall, Hildegard Nikki, Owen, Liusaidh L.J., Livesey, Benjamin B.J., Hanson, Isabel I.M., Adams, Gillian Gwendolen G.G.W., Bodek, Simon, Calvas, Patrick, Castle, Bruce, Clarke, Michael, Deng, Alexander A.T., Edery, Patrick, Fisher, Richard R.S., Gillessen-Kaesbach, Gabriele, Heon, Elise, Hurst, Jane, Josifova, Dragana, Lorenz, Birgit, McKee, Shane, Meire, Françoise, Moore, Anthony Thomas, Parker, Michael W, Reiff, Charlotte C.M., Self, Jay, Tobias, Edward E.S., Verheij, Joke BGM G M J., Willems, Marjolaine, Williams, Denise, Van Heyningen, Veronica, Marsh, Joseph Arthur, and FitzPatrick, David D.R.

Abstract

Purpose: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

17. Loss-of-Function Mutations in the CFH Gene Affecting Alternatively Encoded Factor H-like 1 Protein Cause Dominant Early-Onset Macular Drusen

Author

Taylor, Rachel L., primary, Poulter, James A., additional, Downes, Susan M., additional, McKibbin, Martin, additional, Khan, Kamron N., additional, Inglehearn, Chris F., additional, Webster, Andrew R., additional, Hardcastle, Alison J., additional, Michaelides, Michel, additional, Bishop, Paul N., additional, Clark, Simon J., additional, Black, Graeme C., additional, Black, Graeme, additional, Hall, Georgina, additional, Ingram, Stuart, additional, Taylor, Rachel, additional, Manson, Forbes, additional, Sergouniotis, Panagiotis, additional, Webster, Andrew, additional, Hardcastle, Alison, additional, Plagnol, Vincent, additional, Pontikos, Nikolas, additional, Cheetham, Michael, additional, Arno, Gavin, additional, Fiorentino, Alessia, additional, Inglehearn, Chris, additional, Toomes, Carmel, additional, Ali, Manir, additional, Smith, Claire, additional, Khan, Kamron, additional, Downes, Susan, additional, Yu, Jing, additional, Halford, Stephanie, additional, Broadgate, Suzanne, additional, and van Heyningen, Veronica, additional

Published
2019
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18. Unique noncoding variants upstream of PRDM13 are associated with a spectrum of developmental retinal dystrophies including progressive bifocal chorioretinal atrophy

Author

Silva, Raquel S., primary, Arno, Gavin, additional, Cipriani, Valentina, additional, Pontikos, Nikolas, additional, Defoort-Dhellemmes, Sabine, additional, Kalhoro, Ambreen, additional, Carss, Keren J., additional, Raymond, F. Lucy, additional, Dhaenens, Claire Marie, additional, Jensen, Hanne, additional, Rosenberg, Thomas, additional, van Heyningen, Veronica, additional, Moore, Anthony T., additional, Puech, Bernard, additional, and Webster, Andrew R., additional

Published
2019
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19. Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome

Author

Ansari, Morad, Rainger, Jacqueline, Hanson, Isabel M, Williamson, Kathleen A, Sharkey, Freddie, Harewood, Louise, Sandilands, Angela, Clayton-Smith, Jill, Dollfus, Helene, Bitoun, Pierre, Meire, Francoise, Fantes, Judy, Franco, Brunella, Lorenz, Birgit, Taylor, David S, Stewart, Fiona, Willoughby, Colin E, McEntagart, Meriel, Khaw, Peng Tee, Clericuzio, Carol, Van Maldergem, Lionel, Williams, Denise, Newbury-Ecob, Ruth, Traboulsi, Elias I, Silva, Eduardo D, Madlom, Mukhlis M, Goudie, David R, Fleck, Brian W, Wieczorek, Dagmar, Kohlhase, Juergen, McTrusty, Alice D, Gardiner, Carol, Yale, Christopher, Moore, Anthony T, Russell-Eggitt, Isabelle, Islam, Lily, Lees, Melissa, Beales, Philip L, Tuft, Stephen J, Solano, Juan B, Splitt, Miranda, Hertz, Jens Michael, Prescott, Trine E, Shears, Deborah J, Nischal, Ken K, Doco-Fenzy, Martine, Prieur, Fabienne, Temple, I Karen, Lachlan, Katherine L, Damante, Giuseppe, Morrison, Danny A, van Heyningen, Veronica, FitzPatrick, David R, Ansari, Morad, Rainger, Jacqueline, Hanson, Isabel M., Williamson, Kathleen A., Sharkey, Freddie, Harewood, Louise, Sandilands, Angela, Clayton Smith, Jill, Dollfus, Helene, Bitoun, Pierre, Meire, Francoise, Fantes, Judy, Franco, Brunella, Lorenz, Birgit, Taylor, David S., Stewart, Fiona, Willoughby, Colin E., Mcentagart, Meriel, Khaw, Peng Tee, Clericuzio, Carol, Van Maldergem, Lionel, Williams, Denise, Newbury Ecob, Ruth, Traboulsi, Elias I., Silva, Eduardo D., Madlom, Mukhlis M., Goudie, David R., Fleck, Brian W., Wieczorek, Dagmar, Kohlhase, Juergen, Mctrusty, Alice D., Gardiner, Carol, Yale, Christopher, Moore, Anthony T., Russell Eggitt, Isabelle, Islam, Lily, Lees, Melissa, Beales, Philip L., Tuft, Stephen J., Solano, Juan B., Splitt, Miranda, Hertz, Jens Michael, Prescott, Trine E., Shears, Deborah J., Nischal, Ken K., Doco Fenzy, Martine, Prieur, Fabienne, Temple, I. Karen, Lachlan, Katherine L., Damante, Giuseppe, Morrison, Danny A., Van Heyningen, Veronica, and Fitzpatrick, David R.

Subjects
Male, Genetics and Molecular Biology (all), Eye Diseases, PAX6 Transcription Factor, Mutagenesis and Gene Deletion Techniques, Gene Identification and Analysis, Iris, lcsh:Medicine, Artificial Gene Amplification and Extension, Polymerase Chain Reaction, Biochemistry, axenfeld-rieger syndrome gtpase-activating protein linear skin defects cerebellar-ataxia mental-retardation pax6 gene missense mutations impaired accommodation pitx2 mutations phenotype Science & Technology - Other Topics, Medicine and Health Sciences, Pair 11, lcsh:Science, Aniridia, Comparative Genomic Hybridization, Medicine (all), GTPase-Activating Proteins, Forkhead Transcription Factors, Genomics, Deletion Mutation, Female, Anatomy, Research Article, Human, congenital, hereditary, and neonatal diseases and abnormalities, Cerebellar Ataxia, Ocular Anatomy, Research and Analysis Methods, Human Genomics, Chromosomes, Histone Deacetylases, Ocular System, Intellectual Disability, Genetics, Humans, Genetic Testing, Molecular Biology Techniques, Molecular Biology, Mutation Detection, Homeodomain Proteins, Chromosomes, Human, X, Biochemistry, Genetics and Molecular Biology (all), Chromosomes, Human, Pair 11, lcsh:R, Biology and Life Sciences, Glaucoma, Mutation, Transcription Factors, Agricultural and Biological Sciences (all), eye diseases, Ophthalmology, Mutational Analysis, Genetic Loci, lcsh:Q, sense organs
Abstract

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3′ (telomeric) to PAX6 and one within a gene desert 5′ (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p. Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.

Published
2016

20. A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma

Author

Rainger, Joe, Williamson, Kathleen A, Soares, Dinesh C, Truch, Julia, Kurian, Dominic, Gillessen‐Kaesbach, Gabriele, Seawright, Anne, Prendergast, James, Halachev, Mihail, Wheeler, Ann, McTeir, Lynn, Gill, Andrew C, van Heyningen, Veronica, Davey, Megan G, and FitzPatrick, David R

Subjects
Male, Brief Report, Microfilament Proteins, Protein-Tyrosine Kinases, Ocular Coloboma, Actins, Coloboma, C431 Medical Genetics, Mice, ACTG1, Mutation, eye development, ocular coloboma, Animals, Humans, tissue fusion, Brief Reports, Female, Actin
Abstract

Ocular coloboma (OC) is a defect in optic fissure closure and is a common causeof severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole exome sequencing was used to analyse twelve trios (child affected with OC and both unaffected parents), This identified de novo mutations in ten different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1 and LCP1. Proband-only whole exome sequencing identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra-ocular signs of Baraitser Winter syndrome. We found this mutant protein to be incapable of incorporation into F-actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin-interactions and no further plausibly causative variants were identified in these genes on re-sequencing 380 unrelated individuals with OC.

Published
2017

21. KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

Author

Yeyati, Patricia L., Schiller, Rachel, Mali, Girish, Kasioulis, Ioannis, Kawamura, Akane, Adams, Ian R., Playfoot, Christopher, Gilbert, Nick, van Heyningen, Veronica, Wills, Jimi, von Kriegsheim, Alex, Finch, Andrew, Sakai, Juro, Schofield, Christopher J., Jackson, Ian J., and Mill, Pleasantine

Subjects
Jumonji Domain-Containing Histone Demethylases, Gene Expression, macromolecular substances, Article, Cell Line, Mice, Cilia/metabolism, Journal Article, Morphogenesis, Animals, Humans, Cilia, Gene Expression/physiology, Research Articles, Biological Transport/physiology, Mutation/physiology, Flagella/metabolism, Histone Demethylases, fungi, Biological Transport, Actins, Phenotype, Flagella, Actins/metabolism, Mutation, Jumonji Domain-Containing Histone Demethylases/metabolism, sense organs, Histone Demethylases/metabolism, Morphogenesis/physiology
Abstract

Yeyati et al. demonstrate that the histone demethylase KDM3A acts as a negative regulator of ciliogenesis by modulating actin dynamics, both transcriptionally and by directly binding actin. KDM3A influences local actin networks to restrict intraflagellar transport during ciliogenesis; in its absence, cilia become unstable with abnormal lengths and accumulated intraflagellar transport proteins., Cilia assembly and disassembly are coupled to actin dynamics, ensuring a coherent cellular response during environmental change. How these processes are integrated remains undefined. The histone lysine demethylase KDM3A plays important roles in organismal homeostasis. Loss-of-function mouse models of Kdm3a phenocopy features associated with human ciliopathies, whereas human somatic mutations correlate with poor cancer prognosis. We demonstrate that absence of KDM3A facilitates ciliogenesis, but these resulting cilia have an abnormally wide range of axonemal lengths, delaying disassembly and accumulating intraflagellar transport (IFT) proteins. KDM3A plays a dual role by regulating actin gene expression and binding to the actin cytoskeleton, creating a responsive “actin gate” that involves ARP2/3 activity and IFT. Promoting actin filament formation rescues KDM3A mutant ciliary defects. Conversely, the simultaneous depolymerization of actin networks and IFT overexpression mimics the abnormal ciliary traits of KDM3A mutants. KDM3A is thus a negative regulator of ciliogenesis required for the controlled recruitment of IFT proteins into cilia through the modulation of actin dynamics.

Published
2017

22. Domain disruption and mutation of the bZIP transcription factor, MAF,associated with cataract, ocular anterior segment dysgenesis and coloboma

Author

Jamieson, Robyn V., Perveen, Rahat, Kerr, Bronwyn, Carette, Martin, Yardley, Jill, Heon, Elise, Wirth, M. Gabriela, van Heyningen, Veronica, Donnai, Di, Munier, Francis, Black, Graeme C. M., Jamieson, Robyn V., Perveen, Rahat, Kerr, Bronwyn, Carette, Martin, Yardley, Jill, Heon, Elise, Wirth, M. Gabriela, van Heyningen, Veronica, Donnai, Di, Munier, Francis, and Black, Graeme C. M.

Abstract

Human congenital cataract and ocular anterior segment dysgenesis both demonstrate extensive genetic and phenotypic heterogeneity. We identified a family where ocular developmental abnormalities (cataract, anterior segment dysgenesis and microphthalmia) co-segregated with a translocation, t(5;16)(p15.3;q23.2), in both balanced and unbalanced forms. We hypothesized that this altered the expression of a gene of developmental significance in the human lens and ocular anterior segment. Cloning the 16q23.2 breakpoint demonstrated that it transected the genomic-control domain of MAF, a basic region leucine zipper (bZIP) transcription factor, first identified as an oncogene, which is expressed in vertebrate lens development and regulates the expression of the eye lens crystallins. The homozygous null mutant Maf mouse embryo demonstrates defective lens formation and microphthalmia. Through mutation screening of a panel of patients with hereditary congenital cataract we identified a mutation in MAF in a three-generation family with cataract, microcornea and iris coloboma. The mutation results in the substitution of an evolutionarily highly conserved arginine with a proline at residue 288 (R288P) in the basic region of the DNA-binding domain of MAF. Our findings further implicate MAF/Maf in mammalian lens development and highlight the role of the lens in anterior segment development. The 16q23.2 breakpoint transects the common fragile site, FRA16D, providing a molecular demonstration of a germline break in a common fragile site

Published
2017

23. Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data

Author

Pontikos, Nikolas, Yu, Jing, Moghul, Ismail, Withington, Lucy, Blanco-Kelly, Fiona, Vulliamy, Tom, Wong, Tsz Lun Ernest, Murphy, Cian, Cipriani, Valentina, Fiorentino, Alessia, Arno, Gavin, Greene, Daniel, Jacobsen, Julius O B, Clark, Tristan, Gregory, David S., Nemeth, Andrea M., Halford, Stephanie, Inglehearn, Chris F, Downes, Susan, Black, Graeme C., Webster, Andrew R, Hardcastle, Alison J, Plagnol, Vincent, Ali, Manir, McKibbin, Martin, Poulter, James A., Khan, Kamron, Lord, Emma, Lise, Stefano, Michaelides, Michel, Cheetham, Michael E., and Van Heyningen, Veronica

Subjects
0301 basic medicine, Statistics and Probability, Open platform, Databases, Factual, Computer science, Interface (Java), MEDLINE, Biochemistry, World Wide Web, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Human Phenotype Ontology, Humans, Molecular Biology, Genetic Diseases, Inborn, Computational Biology, Computer Science Applications, Computational Mathematics, 030104 developmental biology, ComputingMethodologies_PATTERNRECOGNITION, Phenotype, Computational Theory and Mathematics, ComputingMethodologies_GENERAL, 030217 neurology & neurosurgery, Software
Abstract

Summary Phenopolis is an open-source web server providing an intuitive interface to genetic and phenotypic databases. It integrates analysis tools such as variant filtering and gene prioritization based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare genetic diseases. Availability and implementation A demo of the website is available at https://phenopolis.github.io . If you wish to install a local copy, source code and installation instruction are available at https://github.com/phenopolis . The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts. Contact n.pontikos@ucl.ac.uk. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2016

24. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, Williamson, Kathleen A, Rainger, Jacqueline K, Wheeler, Ann, Seawright, Anne, De Baere, Elfride, Verdin, Hannah, Bergendahl, L Therese, Quigley, Alan, Rainger, Joe, Dixit, Abhijit, Sarkar, Ajoy, López Laso, Eduardo, Sanchez-Carpintero, Rocio, Barrio, Jesus, Bitoun, Pierre, Prescott, Trine, Riise, Ruth, McKee, Shane, Cook, Jackie, McKie, Lisa, Ceulemans, Berten, Meire, Françoise, Temple, I Karen, Prieur, Fabienne, Williams, Jonathan, Clouston, Penny, Németh, Andrea H, Banka, Siddharth, Bengani, Hemant, Handley, Mark, Freyer, Elisabeth, Ross, Allyson, DDD Study, van Heyningen, Veronica, Marsh, Joseph A, Elmslie, Frances, and FitzPatrick, David R

Subjects
Adult, Male, cerebellar hypoplasia, inositol triphosphate, Adolescent, Cerebellar Ataxia, Protein Conformation, aniridia, Mice, Intellectual Disability, cerebellar vermis, Animals, Humans, Inositol 1,4,5-Trisphosphate Receptors, Lymphocytes, Child, Cells, Cultured, iris, Genes, Dominant, ITPR1, calcium, Microscopy, Confocal, Middle Aged, Pedigree, Mutation, Female, ACTA2
Abstract

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.

Published
2016

25. Correction: Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, primary, Brand, Harrison, additional, Kupchinsky, Zachary A, additional, Bengani, Hemant, additional, Plummer, Lacey, additional, Jones, Takako I, additional, Erdin, Serkan, additional, Williamson, Kathleen A, additional, Rainger, Joe, additional, Stortchevoi, Alexei, additional, Samocha, Kaitlin, additional, Currall, Benjamin B, additional, Dunican, Donncha S, additional, Collins, Ryan L, additional, Willer, Jason R, additional, Lek, Angela, additional, Lek, Monkol, additional, Nassan, Malik, additional, Pereira, Shahrin, additional, Kammin, Tammy, additional, Lucente, Diane, additional, Silva, Alexandra, additional, Seabra, Catarina M, additional, Chiang, Colby, additional, An, Yu, additional, Ansari, Morad, additional, Rainger, Jacqueline K, additional, Joss, Shelagh, additional, Smith, Jill Clayton, additional, Lippincott, Margaret F, additional, Singh, Sylvia S, additional, Patel, Nirav, additional, Jing, Jenny W, additional, Law, Jennifer R, additional, Ferraro, Nalton, additional, Verloes, Alain, additional, Rauch, Anita, additional, Steindl, Katharina, additional, Zweier, Markus, additional, Scheer, Ianina, additional, Sato, Daisuke, additional, Okamoto, Nobuhiko, additional, Jacobsen, Christina, additional, Tryggestad, Jeanie, additional, Chernausek, Steven, additional, Schimmenti, Lisa A, additional, Brasseur, Benjamin, additional, Cesaretti, Claudia, additional, García-Ortiz, Jose E, additional, Buitrago, Tatiana Pineda, additional, Silva, Orlando Perez, additional, Hoffman, Jodi D, additional, Mühlbauer, Wolfgang, additional, Ruprecht, Klaus W, additional, Loeys, Bart L, additional, Shino, Masato, additional, Kaindl, Angela M, additional, Cho, Chie-Hee, additional, Morton, Cynthia C, additional, Meehan, Richard R, additional, van Heyningen, Veronica, additional, Liao, Eric C, additional, Balasubramanian, Ravikumar, additional, Hall, Janet E, additional, Seminara, Stephanie B, additional, Macarthur, Daniel, additional, Moore, Steven A, additional, Yoshiura, Koh-ichiro, additional, Gusella, James F, additional, Marsh, Joseph A, additional, Graham, John M, additional, Lin, Angela E, additional, Katsanis, Nicholas, additional, Jones, Peter L, additional, Crowley, William F, additional, Davis, Erica E, additional, FitzPatrick, David R, additional, and Talkowski, Michael E, additional

Published
2017
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26. Genome-wide linkage and haplotype sharing analysis implicates the MCDR3 locus as a candidate region for a developmental macular disorder in association with digit abnormalities

Author

Cipriani, Valentina, primary, Kalhoro, Ambreen, additional, Arno, Gavin, additional, Silva, Raquel S., additional, Pontikos, Nikolas, additional, Puech, Virginie, additional, McClements, Michelle E., additional, Hunt, David M., additional, van Heyningen, Veronica, additional, Michaelides, Michel, additional, Webster, Andrew R., additional, Moore, Anthony T., additional, and Puech, Bernard, additional

Published
2017
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27. KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

Author

Yeyati, Patricia L., primary, Schiller, Rachel, additional, Mali, Girish, additional, Kasioulis, Ioannis, additional, Kawamura, Akane, additional, Adams, Ian R., additional, Playfoot, Christopher, additional, Gilbert, Nick, additional, van Heyningen, Veronica, additional, Wills, Jimi, additional, von Kriegsheim, Alex, additional, Finch, Andrew, additional, Sakai, Juro, additional, Schofield, Christopher J., additional, Jackson, Ian J., additional, and Mill, Pleasantine, additional

Published
2017
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28. Duplication events downstream ofIRX1cause North Carolina macular dystrophy at the MCDR3 locus

Author

Cipriani, Valentina, primary, Silva, Raquel S., additional, Arno, Gavin, additional, Pontikos, Nikolas, additional, Kalhoro, Ambreen, additional, Valeina, Sandra, additional, Inashkina, Inna, additional, Audere, Mareta, additional, Rutka, Katrina, additional, Puech, Bernard, additional, Michaelides, Michel, additional, van Heyningen, Veronica, additional, Lace, Baiba, additional, Webster, Andrew R, additional, and Moore, Anthony T, additional

Published
2017
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29. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, primary, Brand, Harrison, additional, Kupchinsky, Zachary A, additional, Bengani, Hemant, additional, Plummer, Lacey, additional, Jones, Takako I, additional, Erdin, Serkan, additional, Williamson, Kathleen A, additional, Rainger, Joe, additional, Stortchevoi, Alexei, additional, Samocha, Kaitlin, additional, Currall, Benjamin B, additional, Dunican, Donncha S, additional, Collins, Ryan L, additional, Willer, Jason R, additional, Lek, Angela, additional, Lek, Monkol, additional, Nassan, Malik, additional, Pereira, Shahrin, additional, Kammin, Tammy, additional, Lucente, Diane, additional, Silva, Alexandra, additional, Seabra, Catarina M, additional, Chiang, Colby, additional, An, Yu, additional, Ansari, Morad, additional, Rainger, Jacqueline K, additional, Joss, Shelagh, additional, Smith, Jill Clayton, additional, Lippincott, Margaret F, additional, Singh, Sylvia S, additional, Patel, Nirav, additional, Jing, Jenny W, additional, Law, Jennifer R, additional, Ferraro, Nalton, additional, Verloes, Alain, additional, Rauch, Anita, additional, Steindl, Katharina, additional, Zweier, Markus, additional, Scheer, Ianina, additional, Sato, Daisuke, additional, Okamoto, Nobuhiko, additional, Jacobsen, Christina, additional, Tryggestad, Jeanie, additional, Chernausek, Steven, additional, Schimmenti, Lisa A, additional, Brasseur, Benjamin, additional, Cesaretti, Claudia, additional, García-Ortiz, Jose E, additional, Buitrago, Tatiana Pineda, additional, Silva, Orlando Perez, additional, Hoffman, Jodi D, additional, Mühlbauer, Wolfgang, additional, Ruprecht, Klaus W, additional, Loeys, Bart L, additional, Shino, Masato, additional, Kaindl, Angela M, additional, Cho, Chie-Hee, additional, Morton, Cynthia C, additional, Meehan, Richard R, additional, van Heyningen, Veronica, additional, Liao, Eric C, additional, Balasubramanian, Ravikumar, additional, Hall, Janet E, additional, Seminara, Stephanie B, additional, Macarthur, Daniel, additional, Moore, Steven A, additional, Yoshiura, Koh-ichiro, additional, Gusella, James F, additional, Marsh, Joseph A, additional, Graham, John M, additional, Lin, Angela E, additional, Katsanis, Nicholas, additional, Jones, Peter L, additional, Crowley, William F, additional, Davis, Erica E, additional, FitzPatrick, David R, additional, and Talkowski, Michael E, additional

Published
2017
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30. Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome

Author

Naville, Magali, Ishibashi, Minaka, Ferg, Marco, Bengani, Hemant, Rinkwitz, Silke, Krecsmarik, Monika, Hawkins, Thomas A., Wilson, Stephen W., Manning, Elizabeth, Chilamakuri, Chandra S. R., Wilson, David I., Louis, Alexandra, Lucy Raymond, F., Rastegar, Sepand, Strähle, Uwe, Lenhard, Boris, Bally-Cuif, Laure, van Heyningen, Veronica, FitzPatrick, David R., Becker, Thomas S., Roest Crollius, Hugues, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brain and Mind Research Institute, University of Technology Sydney (UTS), Karlsruhe Institute of Technology (KIT), MRC Human Genetics Unit, MRC Institute of Medical Genetic and Molecular Medicine, Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), C.D.B. Division of Biosciences, Anatomy building UCL, Department of Tumor Biology, The Norwegian Radium Hospital, University of Southampton and University Hospital Southampton NHS Foundation Trust, Centre for Human Development, Stem Cells and Regeneration, MP808, Faculty of Medicine, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, University of Bergen (UIB), 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), Institut des Neurosciences Paris-Saclay (NeuroPSI), University of Bergen (UiB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris

Subjects
Life sciences, biology, Genetic Linkage, DATABASE, Evolution, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Article, DISEASE, Animals, Genetically Modified, Evolution, Molecular, Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Medisinske Fag: 700 [VDP], ddc:570, ELEMENTS, Genetics, Animals, Humans, Selection, Genetic, Zebrafish, GENE-EXPRESSION, Gene Rearrangement, TOOLS, Chromosomes, Human, X, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, GENOMIC SEQUENCES, IN-SITU HYBRIDIZATION, ENHANCERS, Biological sciences, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Enhancer Elements, Genetic, HUMAN CELL-TYPES, CONSERVED SYNTENY
Abstract

Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression., Enhancers regulate the transcription of genes over long genomic distances. Here, the authors show that enhancer function is correlated with maintenance of linkage between non-coding elements and neighbouring genes in the human X chromosome and that enhancers in zebrafish drive expression in a pattern consistent with the expression of a linked gene.

Published
2015
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31. Recurrent heterozygous PAX6missense variants cause severe bilateral microphthalmia via predictable effects on DNA–protein interaction

Author

Williamson, Kathleen A., Hall, H. Nikki, Owen, Liusaidh J., Livesey, Benjamin J., Hanson, Isabel M., Adams, G., 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., Willems, Marjolaine, Williams, Denise, van Heyningen, Veronica, Marsh, Joseph A., and FitzPatrick, David R.

Abstract

Most classical aniridia is caused by PAX6haploinsufficiency. PAX6missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.

Published
2020
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33. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, primary, Williamson, Kathleen A., additional, Rainger, Jacqueline K., additional, Wheeler, Ann, additional, Seawright, Anne, additional, De Baere, Elfride, additional, Verdin, Hannah, additional, Bergendahl, L. Therese, additional, Quigley, Alan, additional, Rainger, Joe, additional, Dixit, Abhijit, additional, Sarkar, Ajoy, additional, López Laso, Eduardo, additional, Sanchez-Carpintero, Rocio, additional, Barrio, Jesus, additional, Bitoun, Pierre, additional, Prescott, Trine, additional, Riise, Ruth, additional, McKee, Shane, additional, Cook, Jackie, additional, McKie, Lisa, additional, Ceulemans, Berten, additional, Meire, Françoise, additional, Temple, I. Karen, additional, Prieur, Fabienne, additional, Williams, Jonathan, additional, Clouston, Penny, additional, Németh, Andrea H., additional, Banka, Siddharth, additional, Bengani, Hemant, additional, Handley, Mark, additional, Freyer, Elisabeth, additional, Ross, Allyson, additional, van Heyningen, Veronica, additional, Marsh, Joseph A., additional, Elmslie, Frances, additional, and FitzPatrick, David R., additional

Published
2016
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35. Functional Assessment of Disease-Associated Regulatory Variants In Vivo Using a Versatile Dual Colour Transgenesis Strategy in Zebrafish

Author

Bhatia, Shipra, primary, Gordon, Christopher T., additional, Foster, Robert G., additional, Melin, Lucie, additional, Abadie, Véronique, additional, Baujat, Geneviève, additional, Vazquez, Marie-Paule, additional, Amiel, Jeanne, additional, Lyonnet, Stanislas, additional, van Heyningen, Veronica, additional, and Kleinjan, Dirk A., additional

Published
2015
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36. Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, Brand, Harrison, Kupchinsky, Zachary A, Bengani, Hemant, Plummer, Lacey, Jones, Takako I, Erdin, Serkan, Williamson, Kathleen A, Rainger, Joe, Stortchevoi, Alexei, Samocha, Kaitlin, Currall, Benjamin B, Dunican, Donncha S, Collins, Ryan L, Willer, Jason R, Lek, Angela, Lek, Monkol, Nassan, Malik, Pereira, Shahrin, Kammin, Tammy, Lucente, Diane, Silva, Alexandra, Seabra, Catarina M, Chiang, Colby, An, Yu, Ansari, Morad, Rainger, Jacqueline K, Joss, Shelagh, Smith, Jill Clayton, Lippincott, Margaret F, Singh, Sylvia S, Patel, Nirav, Jing, Jenny W, Law, Jennifer R, Ferraro, Nalton, Verloes, Alain, Rauch, Anita, Steindl, Katharina, Zweier, Markus, Scheer, Ianina, Sato, Daisuke, Okamoto, Nobuhiko, Jacobsen, Christina, Tryggestad, Jeanie, Chernausek, Steven, Schimmenti, Lisa A, Brasseur, Benjamin, Cesaretti, Claudia, García-Ortiz, Jose E, Buitrago, Tatiana Pineda, Silva, Orlando Perez, Hoffman, Jodi D, Mühlbauer, Wolfgang, Ruprecht, Klaus W, Loeys, Bart L, Shino, Masato, Kaindl, Angela M, Cho, Chie-Hee, Morton, Cynthia C, Meehan, Richard R, van Heyningen, Veronica, Liao, Eric C, Balasubramanian, Ravikumar, Hall, Janet E, Seminara, Stephanie B, Macarthur, Daniel, Moore, Steven A, Yoshiura, Koh-ichiro, Gusella, James F, Marsh, Joseph A, Graham, John M, Lin, Angela E, Katsanis, Nicholas, Jones, Peter L, Crowley, William F, Davis, Erica E, FitzPatrick, David R, and Talkowski, Michael E

Published
2017
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37. Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability

Author

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

39. A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.

Author

Rainger J, Williamson KA, Soares DC, Truch J, Kurian D, Gillessen-Kaesbach G, Seawright A, Prendergast J, Halachev M, Wheeler A, McTeir L, Gill AC, van Heyningen V, Davey MG, and FitzPatrick DR

Subjects
Animals, Female, Humans, Male, Mice, Microfilament Proteins genetics, Mutation genetics, Protein-Tyrosine Kinases genetics, Actins genetics, Coloboma etiology, Coloboma genetics
Abstract

Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole-exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband-only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra-ocular signs of Baraitser-Winter syndrome. We found this mutant protein to be incapable of incorporation into F-actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC., (© 2017 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Published
2017
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40. Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome.

Author

Naville M, Ishibashi M, Ferg M, Bengani H, Rinkwitz S, Krecsmarik M, Hawkins TA, Wilson SW, Manning E, Chilamakuri CS, Wilson DI, Louis A, Lucy Raymond F, Rastegar S, Strähle U, Lenhard B, Bally-Cuif L, van Heyningen V, FitzPatrick DR, Becker TS, and Roest Crollius H

Subjects
Animals, Animals, Genetically Modified, Evolution, Molecular, Gene Rearrangement genetics, Humans, Zebrafish, Chromosomes, Human, X genetics, Enhancer Elements, Genetic genetics, Gene Expression genetics, Genetic Linkage genetics, Selection, Genetic genetics
Abstract

Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression.

Published
2015
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