Avian Binocularity and Adaptation to Nocturnal Environments: Genomic Insights Froma Highly Derived Visual Phenotype Rui Borges Universidade Do Porto - Portugal
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Isyte: Integrated Systems Tool for Eye Gene Discovery
Lens iSyTE: Integrated Systems Tool for Eye Gene Discovery Salil A. Lachke,1,2,3,4 Joshua W. K. Ho,1,4,5 Gregory V. Kryukov,1,4,6 Daniel J. O’Connell,1 Anton Aboukhalil,1,7 Martha L. Bulyk,1,8,9 Peter J. Park,1,5,10 and Richard L. Maas1 PURPOSE. To facilitate the identification of genes associated ther investigation. Extension of this approach to other ocular with cataract and other ocular defects, the authors developed tissue components will facilitate eye disease gene discovery. and validated a computational tool termed iSyTE (integrated (Invest Ophthalmol Vis Sci. 2012;53:1617–1627) DOI: Systems Tool for Eye gene discovery; http://bioinformatics. 10.1167/iovs.11-8839 udel.edu/Research/iSyTE). iSyTE uses a mouse embryonic lens gene expression data set as a bioinformatics filter to select candidate genes from human or mouse genomic regions impli- ven with the advent of high-throughput sequencing, the cated in disease and to prioritize them for further mutational Ediscovery of genes associated with congenital birth defects and functional analyses. such as eye defects remains a challenge. We sought to develop METHODS. Microarray gene expression profiles were obtained a straightforward experimental approach that could facilitate for microdissected embryonic mouse lens at three key devel- the identification of candidate genes for developmental disor- opmental time points in the transition from the embryonic day ders, and, as proof-of-principle, we chose defects involving the (E)10.5 stage of lens placode invagination to E12.5 lens primary ocular lens. Opacification of the lens results in cataract, a leading cause of blindness that affects 77 million persons and fiber cell differentiation. -
A New Mutation in BFSP2 (G1091A) Causes Autosomal Dominant Congenital Lamellar Cataracts
Molecular Vision 2008; 14:1906-1911 <http://www.molvis.org/molvis/v14/a226> © 2008 Molecular Vision Received 17 August 2008 | Accepted 18 October 2008 | Published 24 October 2008 A new mutation in BFSP2 (G1091A) causes autosomal dominant congenital lamellar cataracts Xu Ma,1,2,3 Fei-Feng Li,1,2 Shu-Zhen Wang,4 Chang Gao,1,2 Meng Zhang,2 Si-Quan Zhu4 (The first three authors contributed equally to this work.) 1Graduate School, Peking Union Medical College, Beijing, China; 2Department of Genetics, National Research Institute for Family Planning, Beijing, China; 3WHO Collaborative Center for Research in Human Reproduction, Beijing, China; 4Beijing Tongren Eye Center, Capital Medical University, Beijing, China Purpose: We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital lamellar cataracts and demonstrate the functional analysis with biosoftware of a candidate gene in the family. Methods: Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated by using the Linkage Software after genotyping. A mutation was detected by using gene-specific primers in direct sequencing. Wild type and mutant proteins were analyzed with Online Bio-Software. Results: Affected members of this family had lamellar cataracts. Linkage analysis was obtained at markers D3S2322 (LOD score [Z]=7.22, recombination fraction [θ]=0.0) and D3S1541 (Z=5.42, θ=0.0). Haplotype analysis indicated that the cataract gene was closely linked to these two markers. -
Variants in PAX6, PITX3 and HSF4 Causing Autosomal Dominant Congenital Cataracts ✉ ✉ Vanita Berry 1,2 , Alex Ionides2, Nikolas Pontikos 1,2, Anthony T
www.nature.com/eye ARTICLE OPEN Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts ✉ ✉ Vanita Berry 1,2 , Alex Ionides2, Nikolas Pontikos 1,2, Anthony T. Moore2, Roy A. Quinlan3 and Michel Michaelides 1,2 © Crown 2021 BACKGROUND: Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies. METHODS: Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing. RESULTS: Family A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470–477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case. CONCLUSIONS: We have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract. Eye; https://doi.org/10.1038/s41433-021-01711-x INTRODUCTION consistent with early developmental effects as would be Cataract the opacification of the eye lens is the most common, but anticipated for PAX6 and PITX3 transcription factors. Recently, treatable cause of blindness in the world (https://www.who.int/ we have found two novel mutations in the transcription factors publications-detail/world-report-on-vision). -
Program Nr: 1 from the 2004 ASHG Annual Meeting Mutations in A
Program Nr: 1 from the 2004 ASHG Annual Meeting Mutations in a novel member of the chromodomain gene family cause CHARGE syndrome. L.E.L.M. Vissers1, C.M.A. van Ravenswaaij1, R. Admiraal2, J.A. Hurst3, B.B.A. de Vries1, I.M. Janssen1, W.A. van der Vliet1, E.H.L.P.G. Huys1, P.J. de Jong4, B.C.J. Hamel1, E.F.P.M. Schoenmakers1, H.G. Brunner1, A. Geurts van Kessel1, J.A. Veltman1. 1) Dept Human Genetics, UMC Nijmegen, Nijmegen, Netherlands; 2) Dept Otorhinolaryngology, UMC Nijmegen, Nijmegen, Netherlands; 3) Dept Clinical Genetics, The Churchill Hospital, Oxford, United Kingdom; 4) Children's Hospital Oakland Research Institute, BACPAC Resources, Oakland, CA. CHARGE association denotes the non-random occurrence of ocular coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies and deafness (OMIM #214800). Almost all patients with CHARGE association are sporadic and its cause was unknown. We and others hypothesized that CHARGE association is due to a genomic microdeletion or to a mutation in a gene affecting early embryonic development. In this study array- based comparative genomic hybridization (array CGH) was used to screen patients with CHARGE association for submicroscopic DNA copy number alterations. De novo overlapping microdeletions in 8q12 were identified in two patients on a genome-wide 1 Mb resolution BAC array. A 2.3 Mb region of deletion overlap was defined using a tiling resolution chromosome 8 microarray. Sequence analysis of genes residing within this critical region revealed mutations in the CHD7 gene in 10 of the 17 CHARGE patients without microdeletions, including 7 heterozygous stop-codon mutations. -
Primate Specific Retrotransposons, Svas, in the Evolution of Networks That Alter Brain Function
Title: Primate specific retrotransposons, SVAs, in the evolution of networks that alter brain function. Olga Vasieva1*, Sultan Cetiner1, Abigail Savage2, Gerald G. Schumann3, Vivien J Bubb2, John P Quinn2*, 1 Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, U.K 2 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK 3 Division of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, D-63225 Germany *. Corresponding author Olga Vasieva: Institute of Integrative Biology, Department of Comparative genomics, University of Liverpool, Liverpool, L69 7ZB, [email protected] ; Tel: (+44) 151 795 4456; FAX:(+44) 151 795 4406 John Quinn: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK, [email protected]; Tel: (+44) 151 794 5498. Key words: SVA, trans-mobilisation, behaviour, brain, evolution, psychiatric disorders 1 Abstract The hominid-specific non-LTR retrotransposon termed SINE–VNTR–Alu (SVA) is the youngest of the transposable elements in the human genome. The propagation of the most ancient SVA type A took place about 13.5 Myrs ago, and the youngest SVA types appeared in the human genome after the chimpanzee divergence. Functional enrichment analysis of genes associated with SVA insertions demonstrated their strong link to multiple ontological categories attributed to brain function and the disorders. SVA types that expanded their presence in the human genome at different stages of hominoid life history were also associated with progressively evolving behavioural features that indicated a potential impact of SVA propagation on a cognitive ability of a modern human. -
Genetic Determinants Underlying Rare Diseases Identified Using Next-Generation Sequencing Technologies
Western University Scholarship@Western Electronic Thesis and Dissertation Repository 8-2-2018 1:30 PM Genetic determinants underlying rare diseases identified using next-generation sequencing technologies Rosettia Ho The University of Western Ontario Supervisor Hegele, Robert A. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Rosettia Ho 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Medical Genetics Commons Recommended Citation Ho, Rosettia, "Genetic determinants underlying rare diseases identified using next-generation sequencing technologies" (2018). Electronic Thesis and Dissertation Repository. 5497. https://ir.lib.uwo.ca/etd/5497 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Rare disorders affect less than one in 2000 individuals, placing a huge burden on individuals, families and the health care system. Gene discovery is the starting point in understanding the molecular mechanisms underlying these diseases. The advent of next- generation sequencing has accelerated discovery of disease-causing genetic variants and is showing numerous benefits for research and medicine. I describe the application of next-generation sequencing, namely LipidSeq™ ‒ a targeted resequencing panel for the identification of dyslipidemia-associated variants ‒ and whole-exome sequencing, to identify genetic determinants of several rare diseases. Utilization of next-generation sequencing plus associated bioinformatics led to the discovery of disease-associated variants for 71 patients with lipodystrophy, two with early-onset obesity, and families with brachydactyly, cerebral atrophy, microcephaly-ichthyosis, and widow’s peak syndrome. -
1 Supporting Information for a Microrna Network Regulates
Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia. -
Loss-Of-Function Mutations in RAB18 Cause Warburg Micro Syndrome
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT Loss-of-Function Mutations in RAB18 Cause Warburg Micro Syndrome Danai Bem,1 Shin-Ichiro Yoshimura,2,12 Ricardo Nunes-Bastos,2 Frances F. Bond,3 Manju A. Kurian,1,13 Fatima Rahman,1 Mark T.W. Handley,4 Yavor Hadzhiev,1 Imran Masood,5 Ania A. Straatman-Iwanowska,1,13 Andrew R. Cullinane,1,14 Alisdair McNeill,1,3,15 Shanaz S. Pasha,1 Gail A. Kirby,1 Katharine Foster,6 Zubair Ahmed,7 Jenny E. Morton,3 Denise Williams,3 John M. Graham,8 William B. Dobyns,9 Lydie Burglen,10 John R. Ainsworth,11 Paul Gissen,1,13 Ferenc Mu¨ller,1 Eamonn R. Maher,1,3 Francis A. Barr,2 and Irene A. Aligianis1,3,16,* Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. -
The A–Z of Zika Drug Discovery, Drug Discov Today (2018)
Drug Discovery Today Volume 00, Number 00 June 2018 REVIEWS Teaser Zika clinical outcomes might be nefarious impacting newborns for a lifetime. There is still no drug available to cure Zika. We provide guidance to help understand and advance the search for a cure. KEYNOTE REVIEW – The A Z of Zika drug discovery Reviews 1 1 1 Melina Mottin graduated Melina Mottin , Joyce V.V.B. Borba , Rodolpho C. Braga , in pharmacy and earned her 2,3 4 Master’s degree and PhD at Pedro H.M. Torres , Matheus C. Martini , University of Campinas 4 5 (UNICAMP), Brazil. The Jose Luiz Proenca-Modena , Carla C. Judice , main focus of her studies 5 6 7 was to apply molecular Fabio T.M. Costa , Sean Ekins , Alexander L. Perryman and dynamics simulations and 1,5 other computational Carolina Horta Andrade strategies for a nuclear receptor and its association with drugs and coregulatory proteins, implicated in diabetes. 1 LabMol – Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmacia, Universidade Federal de Melina is currently Research Associate of the OpenZika project, at Federal University of Goias, mainly applying Goias – UFG, Goiânia, GO 74605-170, Brazil 2 virtual screening based on docking and QSAR models to Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-900, Brazil 3 select drug candidates against Zika virus. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK 4 Alexander L. Perryman Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, earned his PhD in Andy Institute of Biology, UNICAMP, Campinas, SP 13083-864, Brazil 5 McCammon’s lab at UCSD. -
Subterranean Mammals Show Convergent Regression in Ocular Genes and Enhancers, Along with Adaptation to Tunneling
RESEARCH ARTICLE Subterranean mammals show convergent regression in ocular genes and enhancers, along with adaptation to tunneling Raghavendran Partha1, Bharesh K Chauhan2,3, Zelia Ferreira1, Joseph D Robinson4, Kira Lathrop2,3, Ken K Nischal2,3, Maria Chikina1*, Nathan L Clark1* 1Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States; 2UPMC Eye Center, Children’s Hospital of Pittsburgh, Pittsburgh, United States; 3Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, United States; 4Department of Molecular and Cell Biology, University of California, Berkeley, United States Abstract The underground environment imposes unique demands on life that have led subterranean species to evolve specialized traits, many of which evolved convergently. We studied convergence in evolutionary rate in subterranean mammals in order to associate phenotypic evolution with specific genetic regions. We identified a strong excess of vision- and skin-related genes that changed at accelerated rates in the subterranean environment due to relaxed constraint and adaptive evolution. We also demonstrate that ocular-specific transcriptional enhancers were convergently accelerated, whereas enhancers active outside the eye were not. Furthermore, several uncharacterized genes and regulatory sequences demonstrated convergence and thus constitute novel candidate sequences for congenital ocular disorders. The strong evidence of convergence in these species indicates that evolution in this environment is recurrent and predictable and can be used to gain insights into phenotype–genotype relationships. DOI: https://doi.org/10.7554/eLife.25884.001 *For correspondence: [email protected] (MC); [email protected] (NLC) Competing interests: The Introduction authors declare that no The subterranean habitat has been colonized by numerous animal species for its shelter and unique competing interests exist. -
Mitoxplorer, a Visual Data Mining Platform To
mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations Annie Yim, Prasanna Koti, Adrien Bonnard, Fabio Marchiano, Milena Dürrbaum, Cecilia Garcia-Perez, José Villaveces, Salma Gamal, Giovanni Cardone, Fabiana Perocchi, et al. To cite this version: Annie Yim, Prasanna Koti, Adrien Bonnard, Fabio Marchiano, Milena Dürrbaum, et al.. mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dy- namics and mutations. Nucleic Acids Research, Oxford University Press, 2020, 10.1093/nar/gkz1128. hal-02394433 HAL Id: hal-02394433 https://hal-amu.archives-ouvertes.fr/hal-02394433 Submitted on 4 Dec 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License Nucleic Acids Research, 2019 1 doi: 10.1093/nar/gkz1128 Downloaded from https://academic.oup.com/nar/advance-article-abstract/doi/10.1093/nar/gkz1128/5651332 by Bibliothèque de l'université la Méditerranée user on 04 December 2019 mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations Annie Yim1,†, Prasanna Koti1,†, Adrien Bonnard2, Fabio Marchiano3, Milena Durrbaum¨ 1, Cecilia Garcia-Perez4, Jose Villaveces1, Salma Gamal1, Giovanni Cardone1, Fabiana Perocchi4, Zuzana Storchova1,5 and Bianca H. -
Rab18 Promotes Lipid Droplet (LD) Growth by Tethering the ER to Lds Through SNARE and NRZ Interactions
Published Online: 24 January, 2018 | Supp Info: http://doi.org/10.1083/jcb.201704184 Article Downloaded from jcb.rupress.org on August 7, 2018 Rab18 promotes lipid droplet (LD) growth by tethering the ER to LDs through SNARE and NRZ interactions Dijin Xu,1* Yuqi Li,1* Lizhen Wu,1* Ying Li,1 Dongyu Zhao,1 Jinhai Yu,1 Tuozhi Huang,1 Charles Ferguson,2 Robert G. Parton,2,3 Hongyuan Yang,4 and Peng Li1 1State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China 2Institute for Molecular Bioscience and 3Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Australia 4School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia Lipid incorporation from endoplasmic reticulum (ER) to lipid droplet (LD) is important in controlling LD growth and intra- cellular lipid homeostasis. However, the molecular link mediating ER and LD cross talk remains elusive. Here, we identi- fied Rab18 as an important Rab guanosine triphosphatase in controlling LD growth and maturation.Rab18 deficiency resulted in a drastically reduced number of mature LDs and decreased lipid storage, and was accompanied by increased ER stress. Rab3GAP1/2, the GEF of Rab18, promoted LD growth by activating and targeting Rab18 to LDs. LD-associated Rab18 bound specifically to the ER-associated NAG-RINT1-ZW10 (NRZ) tethering complex and their associated SNAREs (Syntaxin18, Use1, BNIP1), resulting in the recruitment of ER to LD and the formation of direct ER–LD contact. Cells with defects in the NRZ/SNA RE complex function showed reduced LD growth and lipid storage.