34 results on '"Cheryl Y. Gregory-Evans"'
Search Results
2. Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region
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Colin J. D. Ross, Xiaohua Han, Andrew D. Paterson, Casper Shyr, Care Rare Canada, Michelle Higginson, Victor Pegado, Cheryl Y. Gregory-Evans, Xin (Cynthia) Ye, Wyeth W. Wasserman, Nicole M. Roslin, Deborah Giaschi, Millan S. Patel, Oriol Fornes, Phillip A. Richmond, and Christopher J. Lyons
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genetic structures ,Adolescent ,Genetic Linkage ,Rett syndrome ,Locus (genetics) ,Nerve Tissue Proteins ,Biology ,03 medical and health sciences ,symbols.namesake ,Young Adult ,0302 clinical medicine ,Genetic linkage ,Exome Sequencing ,Genetics ,medicine ,genomics ,Rett Syndrome ,Animals ,Humans ,Strabismus ,Gene ,Genetics (clinical) ,030304 developmental biology ,Aged ,Sequence Deletion ,Aged, 80 and over ,0303 health sciences ,Whole Genome Sequencing ,High-Throughput Nucleotide Sequencing ,Forkhead Transcription Factors ,Middle Aged ,medicine.disease ,Phenotype ,eye diseases ,Pedigree ,DNA binding site ,FOXG1 ,030221 ophthalmology & optometry ,Mendelian inheritance ,symbols ,030217 neurology & neurosurgery ,Genome-Wide Studies - Abstract
Strabismus is a common condition, affecting 1-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis, and a single linkage signal has been identified at chromosome 14q12 with a multipoint LOD score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next generation sequencing and in-depth bioinformatic analyses, a 4bp non-coding deletion was prioritized as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an auto-regulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. The findings of this study indicate that the strabismus phenotype commonly observed within FOXG1 syndrome is separable from the more severe syndromic characteristics. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.Author summaryEye misalignment, or strabismus, can affect up to 4% of individuals. When strabismus is detected early, intervention in young children based on eye patching and/or corrective lenses can be beneficial. In some cases, corrective surgeries are used to align the eyes, with many individuals requiring multiple surgeries over a lifetime. A better understanding of the causes of strabismus may lead to earlier detection as well as improved treatment options. Hippocrates observed that strabismus runs in families over 2,400 years ago, an early recognition of what we now recognize as a portion of cases arising from genetic causes. We describe a large family affected by strabismus and identify a single region on chromosome 14 that may be responsible. The region contains FOXG1, in which mutations are known to cause a severe syndrome, with 84% of affected individuals also having strabismus. We identify a 4bp deletion in the region that appears to auto-regulate when FOXG1 is active. Future study of this genetic alteration may enhance our understanding of the mechanisms of strabismus.
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- 2020
3. An update on the genetics of ocular coloboma
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Cheryl Y. Gregory-Evans, Aisha S ALSomiry, and Kevin Gregory-Evans
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0303 health sciences ,Coloboma ,Eye morphogenesis ,genetic structures ,030305 genetics & heredity ,Ocular Coloboma ,Biology ,Eye ,Precision medicine ,Bioinformatics ,medicine.disease ,eye diseases ,Human genetics ,03 medical and health sciences ,Maldevelopment ,Morphogenesis ,Genetics ,medicine ,Optic Fissure ,Animals ,Humans ,sense organs ,Genetics (clinical) ,030304 developmental biology - Abstract
Ocular coloboma is an uncommon, but often severe, sight-threatening condition that can be identified from birth. This congenital anomaly is thought to be caused by maldevelopment of optic fissure closure during early eye morphogenesis. It has been causally linked to both inherited (genetic) and environmental influences. In particular, as a consequence of work to identify genetic causes of coloboma, new molecular pathways that control optic fissure closure have now been identified. Many more regulatory mechanisms still await better understanding to inform on the development of potential therapies for patients with this malformation. This review provides an update of known coloboma genes, the pathways they influence and how best to manage the condition. In the age of precision medicine, determining the underlying genetic cause in any given patient is of high importance.
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- 2019
4. Targeting Lyn regulates Snail family shuttling and inhibits metastasis
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Ka Mun Nip, Kirsi Ketola, Amina Zoubeidi, Cheryl Y. Gregory-Evans, Kenneth W. Harder, Sebastian Frees, X Shan, Sepideh Vahid, Igor Moskalev, Jennifer L. Bishop, Morgan E. Roberts, and Daksh Thaper
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Biology ,Molecular oncology ,Mice ,03 medical and health sciences ,Growth factor receptor ,Downregulation and upregulation ,LYN ,Cell Line, Tumor ,Neoplasms ,Genetics ,Animals ,Humans ,Molecular Targeted Therapy ,Neoplasm Metastasis ,RNA, Small Interfering ,Cell adhesion ,Molecular Biology ,Transcription factor ,Cell cycle ,Xenograft Model Antitumor Assays ,Cell biology ,Gene Expression Regulation, Neoplastic ,Protein Transport ,src-Family Kinases ,030104 developmental biology ,Tumor progression ,Snail Family Transcription Factors - Abstract
The acquisition of an invasive phenotype by epithelial cells occurs through a loss of cellular adhesion and polarity, heralding a multistep process that leads to metastatic dissemination. Since its characterization in 1995, epithelial-mesenchymal transition (EMT) has been closely linked to the metastatic process. As a defining aspect of EMT, loss of cell adhesion through downregulation of E-cadherin is carried out by several transcriptional repressors; key among them the SNAI family of transcription factors. Here we identify for the first time that Lyn kinase functions as a key modulator of SNAI family protein localization and stability through control of the Vav-Rac1-PAK1 (Vav-Rac1-p21-activated kinase) pathway. Accordingly, targeting Lyn in vitro reduces EMT and in vivo reduces metastasis of primary tumors. We also demonstrate the clinical relevance of targeting Lyn as a key player controlling EMT; patient samples across many cancers revealed a strong negative correlation between Lyn and E-cadherin, and high Lyn expression in metastatic tumors as well as metastasis-prone primary tumors. This work reveals a novel pancancer mechanism of Lyn-dependent control of EMT and further underscores the role of this kinase in tumor progression.
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- 2017
5. Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality
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Elizabeth D. Williams, K McGowan, Miriam S. Butler, Jennifer H. Gunter, Ellca Ratther, Pamela J. Russell, N. Erho, Mohammed Alshalafa, Melanie Lehman, Mannan Nouri, Edward M. Schaeffer, Ladan Fazli, Robert Jeffrey Karnes, P S Rennie, Ashley E. Ross, Brett G. Hollier, Stephen McPherson, Nataly Stylianou, Rajdeep Das, Ralph Buttyan, Philip A. Gregory, Jacqui A. McGovern, Josselin Caradec, Luke A. Selth, E. Davicioni, Brian W.C. Tse, Marianna Volpert, Robert B. Jenkins, Robert B. Den, Martin E. Gleave, Colleen C. Nelson, Mani Roshan-Moniri, M. Takhar, Cheryl Y. Gregory-Evans, Tse, BWC, Volpert, M, Ratther, E, Stylianou, N, Gregory, PA, and Hollier, B. G.
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Male ,0301 basic medicine ,Biochemical recurrence ,PCA3 ,Cancer Research ,Epithelial-Mesenchymal Transition ,medicine.medical_treatment ,Biology ,androgen-targeted ,Metastasis ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Neoplasm Metastasis ,Molecular Biology ,Tissue microarray ,Prostatic Neoplasms ,metastatic progression ,Cancer ,Androgen Antagonists ,medicine.disease ,Survival Analysis ,prostate tumors ,Neuropilin-1 ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Radiation therapy ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Tumor progression ,030220 oncology & carcinogenesis ,Immunology ,Disease Progression ,Cancer research ,Original Article ,Neoplasm Grading ,patient mortality - Abstract
Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa. Refereed/Peer-reviewed
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- 2017
6. A mouse model of aniridia reveals the in vivo downstream targets of Pax6 driving iris and ciliary body development in the eye
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Xianghong Shan, Xia Wang, and Cheryl Y. Gregory-Evans
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Male ,0301 basic medicine ,endocrine system ,PAX6 Transcription Factor ,Iris ,Biology ,Mice ,03 medical and health sciences ,Ciliary body ,medicine ,Animals ,Promoter Regions, Genetic ,Aniridia ,Molecular Biology ,Transcription factor ,Laser capture microdissection ,Genetics ,Phenocopy ,Ciliary Body ,Gene Expression Regulation, Developmental ,medicine.disease ,eye diseases ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,Molecular Medicine ,Female ,sense organs ,PAX6 ,Haploinsufficiency ,Chromatin immunoprecipitation ,Gene Deletion - Abstract
The Pax6 transcription factor is essential for development of the brain, eye, olfactory and endocrine systems. Haploinsufficiency of PAX6 in humans and mice causes the congenital condition aniridia, with defects in each of these organs and systems. Identification of the PAX6 transcription networks driving normal development is therefore critical in understanding the pathophysiology observed with loss-of-function defects. Here we have focused on identification of the downstream targets for Pax6 in the developing iris and ciliary body, where we used laser capture microdissection in mouse eyes from E12.5-E16.5, followed by chromatin immunoprecipitation, promoter-reporter assays and immunohistochemistry. We identified 6 differentially expressed genes between wildtype and Pax6 heterozygous mouse tissues and demonstrated that Bmp4, Tgfβ2, and Foxc1 were direct downstream targets of Pax6 in developing iris/ciliary body. These results improve our understanding of how mutations in Bmp4, Tgfβ2, and Foxc1 result in phenocopies of the aniridic eye disease and provide possible targets for therapeutic intervention.
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- 2017
7. Loss-of-function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish
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Daniel Pouly, Laurence Loeuillet, Joelle Roume, Xianghong Shan, Sophie Saunier, Alexandre Benmerah, Marion Failler, Marijn Stokman, Brigitte Leroy, Jelena Martinovic, Mohammadjavad Paydar, Isabel Filges, Virginie Magry, Marine Alves, Cheryl Y. Gregory-Evans, Benjamin H. Kwok, Marion Delous, John S. Allingham, Madeline Louise Reilly, Julia Tantau, Jacqueline R. Hellinga, Rachel H. Giles, Cécile Jeanpierre, Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Utrecht University [Utrecht], Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), Queen's University [Kingston, Canada], Service de foetopathologie [Béclère], Université Paris-Sud - Paris 11 (UP11)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomie et de Cytologie Pathologiques [Poissy], CHI Poissy-Saint-Germain, Service de génétique [Poissy], University of British Columbia (UBC), University of Basel (Unibas), University Medical Center [Utrecht], This work was supported by the Fondation pour la Recherche Médicale (DEQ20130326532 to SS), the European Union’sSeventh Framework Programme (FP7/2007–2013) grant 305608 (EURenOmics, CJ), the GIS-Institut desMaladies Rares (AMA11025KSA to CJ and SS), the CIHR, NSERC, CCSRI, and FRQS (BK), the SwissNational Science Foundation (SNSF, IF), the Dutch Kidney Foundation KOUNCIL consortium(CP11.18). The Imagine Institute is supported by an ANR grant (ANR-A0-IAHU-01)., European Project: 305608,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EURENOMICS(2012), Université Paris-Sud - Paris 11 (UP11)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Benmerah, Alexandre, and European Consortium for High-Throughput Research in Rare Kidney Diseases - EURENOMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305608 - VALID
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0301 basic medicine ,Male ,Microcephaly ,Fluorescent Antibody Technique ,Kinesins ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Kidney ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Ciliopathies ,0302 clinical medicine ,Loss of Function Mutation ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Zebrafish ,Genetics (clinical) ,Oncogene Proteins ,biology ,Cilium ,General Medicine ,Cell biology ,Pedigree ,Midbody ,Phenotype ,Female ,Kidney Diseases ,General Article ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Congenital Abnormalities ,03 medical and health sciences ,Structure-Activity Relationship ,Ciliogenesis ,[SDV.BDD] Life Sciences [q-bio]/Development Biology ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,Molecular Biology ,Genetic Association Studies ,Cytokinesis ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Kidney metabolism ,medicine.disease ,biology.organism_classification ,[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Disease Models, Animal ,030104 developmental biology ,Genetic Loci ,Genes, Lethal ,030217 neurology & neurosurgery - Abstract
International audience; Mutations in KIF14 have previously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Syndromic microcephaly-RHD was strongly reminiscent of clinical ciliopathies, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells. KIF14 encodes a mitotic kinesin, which plays a key role at the midbody during cytokinesis and has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with fetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses showed that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human fetal tissues further revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips indicating a shared function of KIF14 during brain and kidney development. Subsequently, analysis of a kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos, supporting a potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.
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- 2018
8. Exome sequencing identifies mutations inKIF14as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype
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Karl Heinimann, Sevgi Tercanli, Ekaterina Nosova, Cheryl Y. Gregory-Evans, William T. Gibson, Peter Miny, Jan M. Friedman, Isabel Filges, Elisabeth Bruder, Judith G. Hall, Wyeth W. Wasserman, Benno Röthlisberger, and Katelin N. Townsend
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Genetics ,0303 health sciences ,Candidate gene ,Microcephaly ,Massive parallel sequencing ,Cilium ,Biology ,medicine.disease ,Phenotype ,3. Good health ,03 medical and health sciences ,Ciliopathy ,0302 clinical medicine ,Cancer research ,medicine ,Allele ,030217 neurology & neurosurgery ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology - Abstract
Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.
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- 2013
9. Differentiation of Human Embryonic Stem Cells Using Size-Controlled Embryoid Bodies and Negative Cell Selection in the Production of Photoreceptor Precursor Cells
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Aaron W. Joe, Ishaq A. Viringipurampeer, Xia Wang, Anat Yanai, Christopher Laver, Kevin Gregory-Evans, and Cheryl Y. Gregory-Evans
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Cellular differentiation ,Cell ,Cell Culture Techniques ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Embryoid body ,Biology ,Article ,Cell Line ,chemistry.chemical_compound ,Precursor cell ,medicine ,Humans ,Cell Lineage ,Embryoid Bodies ,Cell Size ,Homeodomain Proteins ,Genetics ,Immunomagnetic Separation ,Gene Expression Profiling ,Cell Differentiation ,Retinal ,Embryonic stem cell ,Chromosome Banding ,Culture Media ,Cell biology ,Gene expression profiling ,medicine.anatomical_structure ,chemistry ,Cell culture ,Karyotyping ,Trans-Activators ,Photoreceptor Cells, Vertebrate - Abstract
We proposed to optimize the retinal differentiation protocols for human embryonic stem cells (hESCs) by improving cell handling. To improve efficiency, we first focused on the production of just one retinal precursor cell type (photoreceptor precursor cells [PPCs]) rather than the production of a range of retinal cells. Combining information from a number of previous studies, in particular the use of a feeder-free culture medium and taurine plus triiodothyronine supplements, we then assessed the values of using size-controlled embryoid bodies (EBs) and negative cell selection (to remove residual embryonic antigen-4-positive hESCs). Using size-controlled 1000 cell EBs, significant improvements were made, in that 78% CRX+ve PPCs could be produced in just 17 days. This could be increased to 93% PPCs through the added step of negative cell selection. Improved efficiency of PPC production will help in efforts to undertake shorter and larger preclinical studies as a prelude to future clinical trials.
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- 2013
10. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis
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Mark O'Driscoll, Anna Lehman, Xianghong Shan, Bruno Maranda, Cheryl Y. Gregory-Evans, Małgorzata J.M. Nowaczyk, Ying Qiao, Chansonette Badduke, Rita Colnaghi, Jiadi Wen, Robert S. Wildin, Jennifer Eichmeyer, Iga Abramowicz, Diana Alcantara, Christopher Dunham, Suzanne M E Lewis, Sally Martell, Hani Bagheri, and Evica Rajcan-Separovic
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0301 basic medicine ,Male ,Candidate gene ,Microcephaly ,Adolescent ,Developmental Disabilities ,Receptors, Cytoplasmic and Nuclear ,lcsh:Medicine ,Chromosome Disorders ,Biology ,Karyopherins ,03 medical and health sciences ,medicine ,Genetics ,Animals ,Humans ,Abnormalities, Multiple ,Child ,Zebrafish ,Gene knockdown ,lcsh:R ,Infant ,Nuclear Proteins ,General Medicine ,Microdeletion syndrome ,biology.organism_classification ,medicine.disease ,Phenotype ,2p15p16.1 microdeletion syndrome ,Hypotonia ,Proto-Oncogene Proteins c-rel ,Repressor Proteins ,030104 developmental biology ,Child, Preschool ,Chromosomes, Human, Pair 2 ,Gene Knockdown Techniques ,Female ,medicine.symptom ,Chromosome Deletion ,Carrier Proteins ,Research Article - Abstract
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients’ lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients’ LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients’ LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.
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- 2016
11. Pax2 regulates a fadd-dependent molecular switch that drives tissue fusion during eye development
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Todd Ferreira, Cheryl Y. Gregory-Evans, Shannon DeMaria, Ishaq A. Viringipurampeer, Xianghong Shan, Mariya Moosajee, Jookyung J. Yoon, Kevin Gregory-Evans, and John Ngai
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Chromatin Immunoprecipitation ,Programmed cell death ,Embryo, Nonmammalian ,Fas-Associated Death Domain Protein ,Necroptosis ,Morphogenesis ,Eye ,Genetics ,medicine ,Animals ,FADD ,Molecular Biology ,Transcription factor ,Zebrafish ,Genetics (clinical) ,Cell Proliferation ,Regulation of gene expression ,biology ,PAX2 Transcription Factor ,Neural tube ,Gene Expression Regulation, Developmental ,Articles ,General Medicine ,Zebrafish Proteins ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Eye development ,sense organs - Abstract
Tissue fusion is an essential morphogenetic mechanism in development, playing a fundamental role in developing neural tube, palate and the optic fissure. Disruption of genes associated with the tissue fusion can lead to congenital malformations, such as spina bifida, cleft lip/palate and ocular coloboma. For instance, the Pax2 transcription factor is required for optic fissure closure, although the mechanism of Pax2 action leading to tissue fusion remains elusive. This lack of information defining how transcription factors drive tissue morphogenesis at the cellular level is hampering new treatments options. Through loss- and gain-of-function analysis, we now establish that pax2 in combination with vax2 directly regulate the fas-associated death domain (fadd) gene. In the presence of fadd, cell proliferation is restricted in the developing eye through a caspase-dependent pathway. However, the loss of fadd results in a proliferation defect and concomitant activation of the necroptosis pathway through RIP1/RIP3 activity, leading to an abnormal open fissure. Inhibition of RIP1 with the small molecule drug necrostatin-1 rescues the pax2 eye fusion defect, thereby overcoming the underlying genetic defect. Thus, fadd has an essential physiological function in protecting the developing optic fissure neuroepithelium from RIP3-dependent necroptosis. This study demonstrates the molecular hierarchies that regulate a cellular switch between proliferation and the apoptotic and necroptotic cell death pathways, which in combination drive tissue morphogenesis. Furthermore, our data suggest that future therapeutic strategies may be based on small molecule drugs that can bypass the gene defects causing common congenital tissue fusion defects.
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- 2012
12. NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration
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Zeinabsadat Mohammadi, Andrew Metcalfe, Abu E. Bashar, Kevin Gregory-Evans, Cheryl Y. Gregory-Evans, Ishaq A. Viringipurampeer, Orson L. Moritz, Anat Yanai, and Olena Sivak
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0301 basic medicine ,Retinal degeneration ,Programmed cell death ,Rhodopsin ,Indoles ,Cell Survival ,Inflammasomes ,Necroptosis ,Biology ,Retinal Cone Photoreceptor Cells ,Photoreceptor cell ,03 medical and health sciences ,Retinal Rod Photoreceptor Cells ,NLR Family, Pyrin Domain-Containing 3 Protein ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Cell Death ,Retinal Degeneration ,Pyroptosis ,Imidazoles ,Inflammasome ,General Medicine ,Bystander Effect ,Articles ,medicine.disease ,Cell biology ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,sense organs ,Rats, Transgenic ,medicine.drug ,Signal Transduction - Abstract
The molecular signaling leading to cell death in hereditary neurological diseases such as retinal degeneration is incompletely understood. Previous neuroprotective studies have focused on apoptotic pathways; however, incomplete suppression of cell death with apoptosis inhibitors suggests that other mechanisms are at play. Here, we report that different signaling pathways are activated in rod and cone photoreceptors in the P23H rhodopsin mutant rat, a model representing one of the commonest forms of retinal degeneration. Up-regulation of the RIP1/RIP3/DRP1 axis and markedly improved survival with necrostatin-1 treatment highlighted necroptosis as a major cell-death pathway in degenerating rod photoreceptors. Conversely, up-regulation of NLRP3 and caspase-1, expression of mature IL-1β and IL-18 and improved cell survival with N-acetylcysteine treatment suggested that inflammasome activation and pyroptosis was the major cause of cone cell death. This was confirmed by generation of the P23H mutation on an Nlrp3-deficient background, which preserved cone viability. Furthermore, Brilliant Blue G treatment inhibited inflammasome activation, indicating that the 'bystander cell death' phenomenon was mediated through the P2RX7 cell-surface receptor. Here, we identify a new pathway in cones for bystander cell death, a phenomenon important in development and disease in many biological systems. In other retinal degeneration models different cell-death pathways are activated, which suggests that the particular pathways that are triggered are to some extent genotype-specific. This also implies that neuroprotective strategies to limit retinal degeneration need to be customized; thus, different combinations of inhibitors will be needed to target the specific pathways in any given disease.
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- 2015
13. Ocular coloboma and high myopia with Hirschsprung disease associated with a novel ZFHX1B missense mutation and trisomy 21
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Kevin Gregory-Evans, Gillian G.W. Adams, Alison Salt, R. Dalton, Cheryl Y. Gregory-Evans, and Helena Vieira
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Male ,Down syndrome ,Eye Diseases ,genetic structures ,Mowat–Wilson syndrome ,DNA Mutational Analysis ,Mutation, Missense ,Aneuploidy ,Biology ,medicine.disease_cause ,Exon ,Myopia ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,Hirschsprung Disease ,Child ,Genetics (clinical) ,Zinc Finger E-box Binding Homeobox 2 ,Homeodomain Proteins ,Genetics ,Mutation ,Coloboma ,Base Sequence ,DNA ,medicine.disease ,eye diseases ,Repressor Proteins ,Karyotyping ,Female ,sense organs ,Down Syndrome ,Trisomy - Abstract
Syndromic Hirschsprung disease has been associated with mutations in ZFHX1B, a Smad-interacting transcriptional repressor protein. Tissue in situ hybridization has demonstrated strong expression of ZFHX1B in the developing eye, suggesting that some mutations in this gene may cause visual loss. However, none of the reported mutations have been associated with an ocular phenotype. We describe a patient with Down syndrome and Hirschsprung disease with high myopia and ocular coloboma affecting the iris and retina. In addition to trisomy 21, a novel, de novo heterozygous A to G transition in exon 8 of the ZFHX1B gene was identified, which results in a R953G amino acid substitution. This abnormality was not seen in a screen of 200 chromosomes from ethnically matched, normal controls. The arginine residue at position 953 is an extremely conserved amino acid throughout evolution. This is the first report associating Hirschsprung disease and severe eye defects with a specific genetic mutation and is the first report of a mutation in ZFHX1B causing a developmental ocular anomaly.
- Published
- 2004
14. Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q
- Author
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Louise Downey, Jamie E Craig, Li Jiang, Geoffrey Woodruff, Cheryl Y. Gregory-Evans, Carmel Toomes, Katherine V. Towns, Michael Parker, Chris F. Inglehearn, Kang Zhang, Richard M. Jackson, David A. Mackey, Richard C. Trembath, Sheila Scott, Graeme C.M. Black, Kevin Gregory-Evans, H.M. Bottomley, and Zhenglin Yang
- Subjects
Male ,Models, Molecular ,Frizzled ,FZD4 ,Molecular Sequence Data ,Receptors, Cell Surface ,Locus (genetics) ,Biology ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Retinal Diseases ,Report ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Amino Acid Sequence ,LDL-Receptor Related Proteins ,Polymorphism, Single-Stranded Conformational ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Base Sequence ,Genetic heterogeneity ,Chromosomes, Human, Pair 11 ,Wnt signaling pathway ,Proteins ,LRP5 ,Exons ,medicine.disease ,Frizzled Receptors ,Introns ,Pedigree ,Protein Structure, Tertiary ,Low Density Lipoprotein Receptor-Related Protein-5 ,TSPAN12 ,Receptors, LDL ,Mutation ,030221 ophthalmology & optometry ,Familial exudative vitreoretinopathy ,Female - Abstract
Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor–related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.
- Published
- 2004
15. Gene structure and tissue expression of human selenoprotein W, SEPW1, and identification of a retroprocessed pseudogene, SEPW1P
- Author
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Kevin Gregory-Evans, Cheryl Y. Gregory-Evans, Margaret Fox, and James Bellingham
- Subjects
Sp1 Transcription Factor ,TATA box ,Pseudogene ,Molecular Sequence Data ,Biophysics ,Gene Expression ,Biology ,Biochemistry ,Exon ,Structural Biology ,Sequence Homology, Nucleic Acid ,Gene expression ,Genetics ,Humans ,Amino Acid Sequence ,Muscle, Skeletal ,Promoter Regions, Genetic ,Selenoproteins ,Gene ,Binding Sites ,Base Sequence ,Gene map ,Myocardium ,Proteins ,TAF9 ,Exons ,Selenoprotein W ,TATA Box ,Molecular biology ,Chromosomes, Human, Pair 1 ,Organ Specificity ,Transcription Initiation Site ,Chromosomes, Human, Pair 19 ,Pseudogenes - Abstract
We have determined that the human SEPW1 (selenoprotein W) gene maps to chromosome 19q13.3, spans approximately 6.3 kb and comprises six exons, in contrast to the previously published five exons. The gene lacks canonical TATA and CAAT boxes, but has numerous Sp1 consensus binding sites upstream of multiple transcription start sites. SEPW1 is expressed in all of the 22 tissues assayed, and shows highest expression in skeletal muscle and heart. Additionally, we have also identified a retroprocessed SEPW1 pseudogene, SEPW1P, which maps to chromosome 1p34-35.
- Published
- 2003
16. Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development
- Author
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Adam Rutherford, Robert J. Lucas, James K. L. Holt, Kevin Gregory-Evans, Matthew D. Hodges, Jane C. Sowden, Lindsay C. Bibb, Cheryl Y. Gregory-Evans, and Emma E. Tarttelin
- Subjects
Transcriptional Activation ,DNA, Complementary ,Time Factors ,Blotting, Western ,Mice, Transgenic ,Cell fate determination ,Biology ,Eye ,Retina ,Mice ,Species Specificity ,Gene expression ,Genetics ,medicine ,Animals ,Humans ,Tissue Distribution ,Molecular Biology ,Transcription factor ,Gene ,In Situ Hybridization ,Genetics (clinical) ,Homeodomain Proteins ,Binding Sites ,Reverse Transcriptase Polymerase Chain Reaction ,General Medicine ,Immunohistochemistry ,Cell biology ,medicine.anatomical_structure ,Trans-Activators ,Eye development ,Homeobox ,sense organs ,Homeotic gene - Abstract
Cone--rod homeobox (CRX), a paired-like homeobox transcription factor, plays a major role in photoreceptor development and maintenance of the retina. Fifteen different mutations in the CRX gene have been identified as a cause of blinding retinal dystrophy. As a step towards characterizing the underlying pathophysiology of disease, temporal and spatial gene expression patterns during human and mouse eye development were investigated for CRX and for downstream retinally expressed genes, postulated to be transactivated by CRX. We found that human CRX was expressed at 10.5 weeks post-conception (p.c.). This was significantly later than observed in mouse development. Immunocytochemistry in human retina showed that CRX protein was not detected until >4 weeks later at 15 weeks p.c., implying that it would be unable to transactivate PDEB, IRBP and arrestin, which were all expressed before 15 weeks. These data therefore eliminate CRX as the major transcriptional activator of these three genes from a wide group of retinal genes that can be transactivated by CRX in vitro. Additionally, PDEB was expressed 2 weeks before CRX whereas murine Pdeb was expressed after Crx, highlighting a potential difference for the role of PDEB in human eye development. Previous data had shown CRX expression in the adult human retina to be photoreceptor-specific; however, we demonstrate that this gene is also expressed in the inner nuclear layer (INL) of the human and mouse retina by in situ hybridization and immunocytochemistry. INL localization of murine Crx was confirmed in rd/rd,cl mice, as in this mouse model the photoreceptors are absent. We have found important differences in the temporal expression of this gene in human and mouse retina, although spatial expression of the CRX gene appears to be conserved. In addition, downstream targets of CRX in vitro might not represent in vivo function during development. These data support concerns about the extent to which we can extrapolate from rodent models regarding embryonic development and disease pathophysiology.
- Published
- 2001
17. Refined genetic and physical positioning of the gene for Doyne honeycomb retinal dystrophy (DHRD)
- Author
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Kevin Gregory-Evans, Emma E. Tarttelin, Margaret Fox, Cheryl Y. Gregory-Evans, Sana Kermani, Alan C. Bird, Catherine Plant, Shomi S. Bhattacharya, and James Bellingham
- Subjects
Genetic Markers ,Male ,Recombination, Genetic ,Yeast artificial chromosome ,Genetics ,Candidate gene ,Genotype ,Contig ,Retinal Degeneration ,Locus (genetics) ,Biology ,Contig Mapping ,Pedigree ,Gene mapping ,Genetic marker ,Genetic linkage ,Chromosomes, Human, Pair 2 ,Humans ,Female ,Lod Score ,Chromosomes, Artificial, Yeast ,Genetics (clinical) ,Sequence Tagged Sites - Abstract
Doyne honeycomb retinal dystrophy (DHRD) is a late-onset autosomal dominant disorder that causes degeneration of the retina and can lead to blindness. We have previously assigned DHRD to a 5-cM region of chromosome 2p16 between marker loci D2S2739 and D2S378. Using sequence-tagged sites (STSs), expressed sequence tags (ESTs) and polymorphic markers within the DHRD region, we have identified 18 yeast artificial chromosomes (YACs) encompassing the DHRD locus, spanning approximately 3 Mb. The YAC contig was constructed by STS content mapping of these YACs and incorporates 13 STSs, including four genes and six polymorphic marker loci. We also report the genetic mapping of two families with a dominant drusen phenotype to the DHRD locus, and genetic refinement of the disease locus to a critical interval flanked by microsatellite marker loci D2S2352 and D2S2251, a distance of approximately 700 kb. These studies exclude a number of candidate genes and provide a resource for construction of a transcriptional map of the region, as a prerequisite to identification of the DHRD disease-causing gene and genes for other diseases mapping in the region, such as Malattia leventinese and Carney complex.
- Published
- 1999
18. Localization of a Gene (CORD7) for a Dominant Cone-Rod Dystrophy to Chromosome 6q
- Author
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Graham E. Holder, Anthony T. Moore, David M. Hunt, Bernhard H. F. Weber, Alan C. Bird, Rosemary E. Kelsell, Marcelle Jay, Cheryl Y. Gregory-Evans, and Kevin Gregory-Evans
- Subjects
Male ,Interphotoreceptor matrix gene ,Letter ,Eye Diseases ,Biology ,Retina ,03 medical and health sciences ,0302 clinical medicine ,Retinitis pigmentosa ,Genetics ,medicine ,Humans ,Genetics(clinical) ,Photoreceptor Cells ,IMPG1 ,Cone-Rod Dystrophy ,Gene ,Genetics (clinical) ,Genes, Dominant ,030304 developmental biology ,Lod score ,0303 health sciences ,Blindness ,Cone-rod dystrophy ,Chromosome ,Genetic linkage ,medicine.disease ,Pedigree ,Electrophysiology ,England ,Haplotypes ,Chromosome 6q ,030221 ophthalmology & optometry ,Chromosomes, Human, Pair 6 ,Female ,Proteoglycans ,Lod Score ,Color Perception ,Microsatellite Repeats - Abstract
We thank the family members for their cooperation in this study. This work was supported by the Wellcome Trust (grant 041905), the Frost Charitable Trust, and the Foundation Fighting Blindness.
- Published
- 1998
19. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans
- Author
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Anthony T. Moore, Jacob Raby, Shomi S. Bhattacharya, Warren Emmett, DeQuincy Prescott, Naushin Waseem, Cheryl Y. Gregory-Evans, and Vanita Berry
- Subjects
Male ,Genotype ,Genetic Linkage ,Clinical Sciences ,Molecular Sequence Data ,Mutation, Missense ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Article ,Cataract ,Exon ,Clinical Research ,Genetic linkage ,Genetics ,medicine ,Missense mutation ,Coding region ,Humans ,Dominant ,Genetic Predisposition to Disease ,Polymorphism ,Eye Disease and Disorders of Vision ,Gene ,Genetics (clinical) ,Genes, Dominant ,Pediatric ,Genetics & Heredity ,Mutation ,Base Sequence ,Human Genome ,Membrane Proteins ,Single Nucleotide ,Exons ,Congenital nuclear cataract ,medicine.disease ,Molecular biology ,eye diseases ,Introns ,Pedigree ,Genes ,Congenital cataracts ,Female ,Missense ,Biotechnology - Abstract
Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron-exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.
- Published
- 2013
20. Clinical utility gene card for: Aniridia
- Author
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Rose Richardson, Veronica van Heyningen, Melanie Hingorani, Cheryl Y. Gregory-Evans, and Mariya Moosajee
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Genotype ,PAX6 Transcription Factor ,Cost-Benefit Analysis ,Nerve Tissue Proteins ,030105 genetics & heredity ,Bioinformatics ,Risk Assessment ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Genetic Testing ,Pathology, Molecular ,Dna diagnosis ,Aniridia ,Gene ,Genetics (clinical) ,Genetic testing ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Human genetics ,Mutation ,Clinical Utility Gene Card ,030221 ophthalmology & optometry ,Medical genetics ,business - Published
- 2016
21. Retina Restored and Brain Abnormalities Ameliorated by Single-Copy Knock-In of Human NR2E1 in Null Mice
- Author
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Wyeth W. Wasserman, Elizabeth M. Simpson, Anthony Mathelier, Kevin Gregory-Evans, Mauro Castellarin, Cheryl Y. Gregory-Evans, Jean-François Schmouth, Kathleen G. Banks, and Robert A. Holt
- Subjects
Male ,Receptors, Cytoplasmic and Nuclear ,Biology ,Retina ,Mice ,Gene knockin ,medicine ,Animals ,Humans ,Gene Knock-In Techniques ,Molecular Biology ,Genetics ,Regulation of gene expression ,Genome ,Neurogenesis ,Brain ,Gene Expression Regulation, Developmental ,Cell Biology ,Articles ,Orphan Nuclear Receptors ,Phenotype ,Olfactory bulb ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Lac Operon ,Regulatory sequence ,Forebrain - Abstract
Nr2e1 encodes a stem cell fate determinant of the mouse forebrain and retina. Abnormal regulation of this gene results in retinal, brain, and behavioral abnormalities in mice. However, little is known about the functionality of human NR2E1. We investigated this functionality using a novel knock-in humanized-mouse strain carrying a single-copy bacterial artificial chromosome (BAC). We also documented, for the first time, the expression pattern of the human BAC, using an NR2E1-lacZ reporter strain. Unexpectedly, cerebrum and olfactory bulb hypoplasia, hallmarks of the Nr2e1-null phenotype, were not fully corrected in animals harboring one functional copy of human NR2E1. These results correlated with an absence of NR2E1-lacZ reporter expression in the dorsal pallium of embryos and proliferative cells of adult brains. Surprisingly, retinal histology and electroretinograms demonstrated complete correction of the retina-null phenotype. These results correlated with appropriate expression of the NR2E1-lacZ reporter in developing and adult retina. We conclude that the human BAC contained all the elements allowing correction of the mouse-null phenotype in the retina, while missing key regulatory regions important for proper spatiotemporal brain expression. This is the first time a separation of regulatory mechanisms governing NR2E1 has been demonstrated. Furthermore, candidate genomic regions controlling expression in proliferating cells during neurogenesis were identified.
- Published
- 2012
22. Single choroideremia gene in nonmammalian vertebrates explains early embryonic lethality of the zebrafish model of choroideremia
- Author
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Merrin Tulloch, José B. Pereira-Leal, Rudi A. Baron, Mariya Moosajee, Cheryl Y. Gregory-Evans, Miguel C. Seabra, and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
- Subjects
Gene isoform ,Retinal degeneration ,Embryo, Nonmammalian ,CLAWED FROGS ,Immunoblotting ,Protein Prenylation ,Embryonic Development ,Apoptosis ,Choroideremia ,Retina ,Gene product ,Animals, Genetically Modified ,Evolution, Molecular ,medicine ,In Situ Nick-End Labeling ,Animals ,Zebrafish ,Loss function ,Adaptor Proteins, Signal Transducing ,Genetics ,biology ,IDENTIFICATION ,Retinal Degeneration ,NONSENSE MUTATIONS ,SUPERFAMILY ,DEGENERATION ,Zebrafish Proteins ,biology.organism_classification ,medicine.disease ,COMPONENT-A ,EVOLUTION ,Disease Models, Animal ,Phenotype ,MUTANTS ,rab GTP-Binding Proteins ,RAB GERANYLGERANYL TRANSFERASE ,ESCORT PROTEIN-1 ,Embryo Loss ,Protein prenylation ,Genes, Lethal ,Rab ,Photoreceptor Cells, Vertebrate ,Subcellular Fractions - Abstract
PURPOSE. Mutations of the CHM gene underlie the X-linked chorioretinal degeneration choroideremia (CHM). The affected gene product, Rab Escort Protein (REP) 1, mediates the post-translational prenyl modification of Rab GTPases. In patients with CHM, the related REP2 partially compensates for the loss of function of REP1. The objective of this investigation was to study the natural history of disease in a zebrafish model of CHM. METHODS. Zebrafish chm(-/-) were bred and subjected to extensive histologic analysis and TUNEL assays, and cellular extracts were used for immunoblot and in vitro prenylation assays. A detailed evolutionary analysis was performed on the REP family. RESULTS. The retina of chm(-/-) zebrafish develops normally for the first 4 days postfertilization (dpf) but that catastrophic multilayer degeneration synchronous with severe multisystem disease follows. Mean survival time is 4.8 dpf. At the onset of generalized disease, a significant reduction in rep expression levels and activity, with unprenylated rabs accumulating in the cytosol was demonstrated. Extensive bioinformatic analysis of the REP family of proteins revealed a single rep isoform in fish and other nonmammalian vertebrates and invertebrates that is similar to mammalian REP1. CONCLUSIONS. REP1 appears to be the ancestral gene in the family, whereas the intronless REP2 gene is restricted to the mammalian lineage. The results of this study propose that in chm(-/-) zebrafish, maternally derived rep allows initial successful development of the embryo, but its gradual loss leads to multisystem disease and invariably to lethality. In its current form, the chm(-/-) zebrafish has limited usefulness. (Invest Ophthalmol Vis Sci. 2009;50:3009-3016) DOI: 10.1167/iovs.08-2755 publishersversion published
- Published
- 2009
23. Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease
- Author
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Cheryl Y. Gregory-Evans, Miguel C. Seabra, Charles D. Ellis, Mariya Moosajee, and Kevin Gregory-Evans
- Subjects
Embryo, Nonmammalian ,Paromomycin ,Nonsense mutation ,Bioinformatics ,In vivo ,Retinitis pigmentosa ,Chlorocebus aethiops ,Genetics ,medicine ,Animals ,Molecular Biology ,Zebrafish ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing ,Protein Synthesis Inhibitors ,Coloboma ,biology ,Dose-Response Relationship, Drug ,Genetic heterogeneity ,Molecular pathology ,Aminoglycoside ,PAX2 Transcription Factor ,Gene Expression Regulation, Developmental ,Eye Diseases, Hereditary ,General Medicine ,Zebrafish Proteins ,biology.organism_classification ,medicine.disease ,Disease Models, Animal ,Phenotype ,Codon, Nonsense ,Protein Biosynthesis ,COS Cells ,Laminin ,Gentamicins - Abstract
The extensive molecular genetic heterogeneity seen with inherited eye disease is a major barrier to the development of gene-based therapeutics. The underlying molecular pathology in a considerable proportion of these diseases however are nonsense mutations leading to premature termination codons. A therapeutic intervention targeted at this abnormality would therefore potentially be relevant to a wide range of inherited eye diseases. We have taken advantage of the ability of aminoglycoside drugs to suppress such nonsense mutations and partially restore full-length, functional protein in a zebrafish model of choroideraemia (chm(ru848); juvenile chorio-retinal degeneration) and in two models of ocular coloboma (noi(tu29a) and gup(m189); congenital optic fissure closure defects). In vitro cell-based assays showed significant readthrough with two drugs, gentamicin and paromomycin, which was confirmed by western blot and in vitro prenylation assays. The presence of either aminoglycoside during zebrafish development in vivo showed remarkable prevention of mutant ocular phenotypes in each model and a reduction in multisystemic defects leading to a 1.5-1.7-fold increase in survival. We also identified a significant reduction in abnormal cell death shown by TUNEL assay. To test the hypothesis that optic fissure closure was apoptosis-dependent, the anti-apoptotic agents, curcumin and zVAD-fmk, were tested in gup(m189) embryos. Both drugs were found to reduce the size of the coloboma, providing molecular evidence that cell death is required for optic fissure remodelling. These findings draw attention to the value of zebrafish models of eye disease as useful preclinical drug screening tools in studies to identify molecular mechanisms amenable to therapeutic intervention.
- Published
- 2008
24. SNP genome scanning localizes oto-dental syndrome to chromosome 11q13 and microdeletions at this locus implicate FGF3 in dental and inner-ear disease and FADD in ocular coloboma
- Author
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Georges Wackens, Cheryl Y. Gregory-Evans, Mariya Moosajee, Neil Vargesson, Agnès Bloch-Zupan, Franz Rüschendorf, Laurence Game, Kevin Gregory-Evans, Donna S. Mackay, Lourdes Aparecida Martins dos Santos-Pinto, Matthew D. Hodges, Imperial College London, Universite Louis Pasteur, Max Delbrück Center for Molecular Medicine, Universidade de São Paulo (USP), Free University of Brussels, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Embryo, Nonmammalian ,Genetic Linkage ,Fas-Associated Death Domain Protein ,Organogenesis ,DNA Mutational Analysis ,Fibroblast Growth Factor 3 ,Labyrinth Diseases ,Loss of Heterozygosity ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,Eye ,Polymorphism, Single Nucleotide ,Craniofacial Abnormalities ,Loss of heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Genetic linkage ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Zebrafish ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Coloboma ,Chromosomes, Human, Pair 11 ,Otodental syndrome ,Haplotype ,Stomatognathic Diseases ,Chromosome Mapping ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Syndrome ,General Medicine ,medicine.disease ,Molecular biology ,Pedigree ,Female ,Haploinsufficiency ,Gene Deletion ,030217 neurology & neurosurgery - Abstract
Made available in DSpace on 2022-04-29T08:43:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-10-15 We ascertained three different families affected with oto-dental syndrome, a rare but severe autosomal-dominant craniofacial anomaly. All affected patients had the unique phenotype of grossly enlarged molar teeth (globodontia) segregating with a high-frequency sensorineural hearing loss. In addition, ocular coloboma segregated with disease in one family (oculo-oto-dental syndrome). A genome-wide scan was performed using the Affymetrix GeneChip10K 2.0 Array. Parametric linkage analysis gave a single LOD score peak of 3.9 identifying linkage to chromosome 11q13. Haplotype analysis revealed three obligatory recombination events defining a 4.8 Mb linked interval between D11S1889 and SNP rs2077955. Higher resolution mapping and Southern blot analysis in each family identified overlapping hemizygous microdeletions. SNP expression analysis and real-time quantitative RT-PCR in patient lymphoblast cell lines excluded a positional effect on the flanking genes ORAOV1, PPFIA1 and CTTN. The smallest 43 kb deletion resulted in the loss of only one gene, FGF3, which was also deleted in all other otodental families. These data suggest that FGF3 haploinsufficiency is likely to be the cause of otodental syndrome. In addition, the Fas-associated death domain (FADD) gene was also deleted in the one family segregating ocular coloboma. Spatiotemporal in situ hybridization in zebrafish embryos established for the first time that fadd is expressed during eye development. We therefore propose that FADD haploinsufficiency is likely to be responsible for ocular coloboma in this family. This study therefore implicates FGF3 and FADD in human craniofacial disease. © The Author 2007. Published by Oxford University Press. All rights reserved. Department of Clinical Neuroscience Imperial College London, St Dunstan's Road, London W6 8RP CSC-IC Microarray Centre/Genome Centre Imperial College London, St Dunstan's Road, London W6 8RP NHLI Imperial College London, St Dunstan's Road, London SW7 2AZ Faculte de Chirgurgie Dentaire Universite Louis Pasteur, Strasbourg F-67000 Max Delbrück Center for Molecular Medicine, D-13092 Berlin Department of Paediatric Dentistry Araraquara Dental School University of São Paulo State, São Paulo 14801-903 Department of Oral and Maxillofacial Surgery Free University of Brussels, 1050 Elsene
- Published
- 2007
25. A new family of Greek origin maps to the CRD locus for autosomal dominant cone-rod dystrophy on 19q
- Author
-
James Bellingham, Shomi S. Bhattacharya, Aphrodite Loutradis-Anagnostou, David A.R. Bessant, Constantine Rougas, Myrto Papaioannou, Annette M. Payne, Angeliki Balassopoulou, and Cheryl Y. Gregory-Evans
- Subjects
Male ,Retinal degeneration ,Genetic Linkage ,Color Vision Defects ,Locus (genetics) ,Biology ,Retina ,Genetic determinism ,Gene mapping ,Genetic linkage ,Genetics ,medicine ,Humans ,Gene ,Genetics (clinical) ,Genes, Dominant ,Chromosome 19q13 ,Greece ,Cone-rod dystrophy ,Retinal Degeneration ,Haplotype ,Chromosome Mapping ,Dystrophy ,medicine.disease ,eye diseases ,Pedigree ,Haplotypes ,Female ,Chromosomes, Human, Pair 19 ,Research Article - Abstract
3 páginas, 2 figuras, 1 tabla.-- et al., Retinal photoreceptor dystrophies (RD) are a highly heterogeneous group of genetic disorders of the retina, representing the most frequently inherited form of visual handicap, affecting approximately 1.5 million people world wide. To date, more than 40 genetic loci have been implicated in RD. One of them, the CORD2 locus, for an autosomal dominant form of cone-rod dystrophy (CRD), maps to chromosome 19q and has previously been reported in a single large family of British origin. We now report a new family with severe early onset CRD, phenotypically very similar to the British family, which also maps to 19q, but is of Greek origin. Haplotype data of the Greek family showed no recombination between and including markers D19S219 and D19S246 and linkage analysis gave a lod score of 2.7 (at theta=0) with marker D19S412, confirming the data obtained in the British family., M Papaioannou is a fellow of the National Greek Scholarship Foundation. Drs D Bessant and A Payne are funded by the Medical Research Council of the UK (grant No G9301094).
- Published
- 1998
26. Ocular coloboma: a reassessment in the age of molecular neuroscience
- Author
-
Stephanie Halford, M J Williams, Kevin Gregory-Evans, and Cheryl Y. Gregory-Evans
- Subjects
PAX6 Transcription Factor ,genetic structures ,Genetic counseling ,Eye disease ,Genetic Counseling ,Disease ,Review ,Biology ,Environment ,Bioinformatics ,Eye ,Anophthalmos ,Genetics ,medicine ,Animals ,Humans ,Microphthalmos ,Paired Box Transcription Factors ,Hedgehog Proteins ,Craniofacial ,Eye Proteins ,Genetics (clinical) ,Homeodomain Proteins ,Coloboma ,medicine.disease ,eye diseases ,Repressor Proteins ,Gene Expression Regulation ,Genetic redundancy ,Trans-Activators ,sense organs - Abstract
Congenital colobomata of the eye are important causes of childhood visual impairment and blindness. Ocular coloboma can be seen in isolation and in an impressive number of multisystem syndromes, where the eye phenotype is often seen in association with severe neurological or craniofacial anomalies or other systemic developmental defects. Several studies have shown that, in addition to inheritance, environmental influences may be causative factors. Through work to identify genes underlying inherited coloboma, significant inroads are being made into understanding the molecular events controlling closure of the optic fissure. In general, severity of disease can be linked to the temporal expression of the gene, but this is modified by factors such as tissue specificity of gene expression and genetic redundancy.
- Published
- 2004
27. Expression of opsin genes early in ocular development of humans and mice
- Author
-
Mark W. Hankins, Emma E. Tarttelin, James Bellingham, Dominic J. Wells, Robert J. Lucas, Russell G. Foster, Lindsay C. Bibb, Cheryl Y. Gregory-Evans, and Kevin Gregory-Evans
- Subjects
Melanopsin ,Opsin ,genetic structures ,Eye ,Embryonic and Fetal Development ,Mice ,Cellular and Molecular Neuroscience ,Gene expression ,medicine ,Animals ,Humans ,Encephalopsin ,Gene ,reproductive and urinary physiology ,Regulation of gene expression ,Genetics ,Retina ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Rod Opsins ,Gene Expression Regulation, Developmental ,Sensory Systems ,eye diseases ,Cell biology ,Ophthalmology ,medicine.anatomical_structure ,Rhodopsin ,biology.protein ,sense organs - Abstract
We have compared the onsets of expression of the classical visual opsins with those of the non-rod, non-cone opsins in foetal and post-natal eye tissue from mice and humans. Mouse Rgr-opsin, peropsin, encephalopsin and melanopsin are all expressed in foetal development by E11.5, unlike the murine rod and cone opsins that exhibit post-natal expression, e.g. P1 for ultraviolet cone opsin and P5 for rod opsin. Human non-rod, non-cone opsins are also all expressed early, by 8.6 weeks post-conception. The implications of these observations are discussed with regard to the possible functions of these opsins at early stages of ocular development.
- Published
- 2003
28. Molecular genetic heterogeneity in autosomal dominant drusen
- Author
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Cheryl Y. Gregory-Evans, Emma E. Tarttelin, Alan C. Bird, Kevin Gregory-Evans, Richard G. Weleber, James Blackburn, and Michael L. Klein
- Subjects
Adult ,Male ,genetic structures ,HpaII ,Genetic Linkage ,Locus (genetics) ,Retinal Drusen ,Drusen ,Biology ,Polymorphism, Single Nucleotide ,Cohort Studies ,Genetic linkage ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Genes, Dominant ,Extracellular Matrix Proteins ,Splice site mutation ,Genetic heterogeneity ,Haplotype ,Genetic Variation ,Original Articles ,Macular degeneration ,Middle Aged ,medicine.disease ,eye diseases ,Pedigree ,Radiography ,Haplotypes ,Chromosomes, Human, Pair 2 ,Chromosomes, Human, Pair 6 ,Female - Abstract
OBJECTIVEAutosomal dominant drusen is of particular interest because of its phenotypic similarity to age related macular degeneration. Currently, mutation R345W ofEFEMP1 and, in a single pedigree, linkage to chromosome 6q14 have been causally related to the disease. We proposed to investigate and quantify the roles ofEFEMP1 and the 6q14 locus in dominant drusen patients from the UK and USA.DESIGNMolecular genetic analysis.PARTICIPANTSTen unrelated families and 17 young drusen patients.MAIN OUTCOME MEASURESExons 1 and 2 of EFEMP1 were characterised by 5′ rapid amplification of cDNA ends and direct sequencing. Exons 1-12 ofEFEMP1 were then investigated for mutation by direct sequencing. A HpaII restriction digest test was constructed to detect the EFEMP1R345W mutation. Marker loci spanning the two dominant drusen linked loci were used to generate haplotype data.RESULTSOnly seven of the 10 families (70%) and one of the 17 sporadic patients (6%) had the R345W mutation. The HpaII restriction digest test was found to be a reliable and quick method for detecting this. No other exonic or splice site mutation was identified. Of the three families without EFEMP1 mutation, two were linked to the 2p16 region.CONCLUSIONSEFEMP1R345W accounts for only a proportion of the dominant drusen phenotype. Importantly, other families linked to chromosome 2p16 raise the possibility of EFEMP1 promoter sequence mutation or a second dominant drusen gene at this locus. Preliminary haplotype data suggest that the disease gene at the 6q14 locus is responsible for only a minority of dominant drusen cases.
- Published
- 2001
29. Characterisation of the CRX Gene; Identification of Alternatively Spliced 5’ Exons and 3’ Sequence
- Author
-
Cheryl Y. Gregory-Evans, Matthew D. Hodges, and Kevin Gregory-Evans
- Subjects
Genetics ,Exon ,genetic structures ,RPE65 ,RNA splicing ,Homeobox ,Dystrophy ,Chromosome ,sense organs ,Biology ,Gene ,Transcription factor ,eye diseases - Abstract
The cone-rod homeobox gene (CRX) is a paired-like transcription factor belonging to the otd/Otx family that is essential for the maintenance and development of photoreceptors1-5. The gene has been mapped to chromosome 19ql3.3 and has been implicated in autosomal dominant cone-rod dystrophy (adCRD)1,2,6 and Leber’s congenital amaurosis (LCA)7,8,9. adCRD is characterised by an initial loss of colour vision and visual acuity followed by nyctlopia, progressive loss of peripheral vision and advancing retinal pigmentation10, LCA is defined as total blindness at birth or soon afterwards, involving retinal dystrophy and is nearly always recessively inherited11. There is distinct heterogeneity between adCRD and LCA both clinically and genetically. Mutations in RETGC-1,12 RPE65,13 and AIPLI 14 have been attributed to LCA, with linkage to a further three loci and at least four loci have been linked to adCRD1. The CRX protein itself has been shown to interact with NRL,15 p300/CBP,16 RX,17 and phosducin18. This implies that mutations in multiple loci may therefore cause adCRD or LCA.
- Published
- 2001
30. Microsatellite markers for the cone-rod retinal dystrophy gene, CRX, on 19q13.3
- Author
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Cheryl Y. Gregory-Evans, James Bellingham, and Kevin Gregory-Evans
- Subjects
Retinal degeneration ,Genetic Markers ,Molecular Sequence Data ,Biology ,Retinal Cone Photoreceptor Cells ,Heterozygote Detection ,Retinal Rod Photoreceptor Cells ,Genetics ,medicine ,Humans ,Cone-Rod Dystrophy ,Gene ,Genetics (clinical) ,Polymorphism, Genetic ,Genetic Carrier Screening ,Retinal Degeneration ,Genes, Homeobox ,Chromosome Mapping ,medicine.disease ,Cell biology ,Microsatellite ,Chromosomes, Human, Pair 19 ,Microsatellite Repeats ,Research Article - Published
- 1998
31. A polymorphic dinucleotide repeat in the 5' flanking region of the human interleukin 11 (IL11) gene
- Author
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James Bellingham, Cheryl Y. Gregory-Evans, and Kevin Gregory-Evans
- Subjects
Genetics ,DNA, Complementary ,Polymorphism, Genetic ,Base Sequence ,Immunology ,5' flanking region ,Molecular Sequence Data ,Biology ,Dinucleotide Repeat ,Interleukin-11 ,Molecular biology ,Human genetics ,Interleukin 11 ,Humans ,Base sequence ,Allele ,Dinucleotide Repeats ,Gene ,Alleles - Published
- 1998
32. Assignment<footref rid='foot01'>1</footref> of BCL2L11 to human chromosome band 2p13 with somatic cell and radiation hybrids
- Author
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Shomi S. Bhattacharya, Neil D. Ebenezer, Cheryl Y. Gregory-Evans, Stephanie Halford, and S Murray
- Subjects
Genetics ,Chromosome Band ,Gene mapping ,BCL2L11 ,Apoptosis ,Somatic cell ,Bcl-2 family ,Radiation Hybrids ,Biology ,Molecular Biology ,Genetics (clinical) - Published
- 2001
33. [Untitled]
- Author
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Clare Huxley, Tanya Tolmachova, Amanda McGuigan, Alistair N. Hume, Miguel C. Seabra, José S. Ramalho, and Cheryl Y. Gregory-Evans
- Subjects
Genetics ,endocrine system ,0303 health sciences ,Biology ,Molecular biology ,Fusion protein ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Chromosome 18 ,030220 oncology & carcinogenesis ,Complementary DNA ,Northern blot ,Rab ,RAB27 ,Gene ,Genetics (clinical) ,030304 developmental biology - Abstract
Rab GTPases are regulators of intracellular membrane traffic. The Rab27 subfamily consists of Rab27a and Rab27b. Rab27a has been recently implicated in Griscelli Disease, a disease combining partial albinism with severe immunodeficiency. Rab27a plays a key role in the function of lysosomal-like organelles such as melanosomes in melanocytes and lytic granules in cytotoxic T lymphocytes. Little is known about Rab27b. The human RAB27B gene is organised in six exons, spanning about 69 kb in the chromosome 18q21.1 region. Exon 1 is non-coding and is separated from the others by 49 kb of DNA and exon 6 contains a long 3' untranslated sequence (6.4 kb). The mouse Rab27b cDNA shows 95% identity with the human cDNA at the protein level and maps to mouse chromosome 18. The mouse mRNA was detected in stomach, large intestine, spleen and eye by RT-PCR, and in heart, brain, spleen and kidney by Northern blot. Transient over-expression of EGF-Rab27b fusion protein in cultured melanocytes revealed that Rab27b is associated with melanosomes, as observed for EGF-Rab27a. Our results indicate that the Rab27 subfamily of Ras-like GTPases is highly conserved in mammals. There is high degree of conservation in sequence and gene structure between RAB27A and RAB27B genes. Exogenous expression of Rab27b in melanocytes results in melanosomal association as observed for Rab27a, suggesting the two Rab27 proteins are functional homologues. As with RAB27A in Griscelli Disease, RAB27B may be also associated with human disease mapping to chromosome 18.
- Published
- 2001
34. Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene (CRX) Essential for Maintenance of the Photoreceptor
- Author
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Lap-Chee Tsui, Stephen W. Scherer, Roderick R. McInnes, Constance L. Cepko, Aphrodite Loutradis-Anagnostou, David Ng, Alessandra M.V. Duncan, Samuel G. Jacobson, Jo Anne Herbrick, Myrto Papaioannou, Shomi S. Bhattacharya, Carol L. Freund, Lynda Ploder, James Bellingham, Jens Looser, Cheryl Y. Gregory-Evans, Takahisa Furukawa, Foundation Fighting Blindness, Canada Foundation for Innovation, Medical Council of Canada, Wellcome Trust, Howard Hughes Medical Institute, National Human Genome Research Institute (US), Genome Canada, and National Institutes of Health (US)
- Subjects
Retinal degeneration ,Adult ,Male ,Molecular Sequence Data ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Retina ,Conserved sequence ,03 medical and health sciences ,0302 clinical medicine ,Retinitis pigmentosa ,medicine ,Humans ,Point Mutation ,Photoreceptor Cells ,Amino Acid Sequence ,RNA, Messenger ,Frameshift Mutation ,Conserved Sequence ,030304 developmental biology ,Genes, Dominant ,Genetics ,Homeodomain Proteins ,0303 health sciences ,Base Sequence ,Sequence Homology, Amino Acid ,Biochemistry, Genetics and Molecular Biology(all) ,Point mutation ,Retinal Degeneration ,Genes, Homeobox ,Chromosome Mapping ,medicine.disease ,3. Good health ,Pedigree ,Organ Specificity ,030221 ophthalmology & optometry ,Trans-Activators ,Homeobox ,Female ,Haploinsufficiency ,Transcription Factor Gene ,Chromosomes, Human, Pair 19 ,Visual phototransduction ,Transcription Factors - Abstract
Genes associated with inherited retinal degeneration have been found to encode proteins required for phototransduction, metabolism, or structural support of photoreceptors. Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form of cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of the recognition helix is replaced by alanine (E80A). In another CRD family, a 1 bp deletion (E168 [delta1 bp]) within a novel sequence, the WSP motif, predicts truncation of the C-terminal 132 residues of CRX. Mutations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for the maintenance of mammalian photoreceptors, This work was supported by the RP Foundation of Canada (R. R. M.), the Foundation Fighting Blindness (R. R. M. and S. G. J.), the Canadian Genetic Disease Network (R. R. M. and A. D.), the Medical Research Council of Canada (R. R. M.), The Wellcome Trust (043825/Z/95) and the Human Genome Mapping Resource Centre (C. Y. G.-E. and S. S. B.), the Howard Hughes Medical Institute and NIH R01 EY0 8064 (C. L. C.), the Canadian Genome Analysis and Technology Genome Resource Facility (S. W. S. and L.-C. T.), the NIH/NEI (EY05627) (S. G. J.), and the Greek National Scholarship Foundation (M. P.). R. R. M. and L.-C. T. are International Research Scholars of the Howard Hughes Medical Institute.
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