BBS6, BBS10, and BBS12 Form a Complex with CCT/Tric Family Chaperonins and Mediate Bbsome Assembly
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Educational Paper Ciliopathies
Eur J Pediatr (2012) 171:1285–1300 DOI 10.1007/s00431-011-1553-z REVIEW Educational paper Ciliopathies Carsten Bergmann Received: 11 June 2011 /Accepted: 3 August 2011 /Published online: 7 September 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Cilia are antenna-like organelles found on the (NPHP) . Ivemark syndrome . Meckel syndrome (MKS) . surface of most cells. They transduce molecular signals Joubert syndrome (JBTS) . Bardet–Biedl syndrome (BBS) . and facilitate interactions between cells and their Alstrom syndrome . Short-rib polydactyly syndromes . environment. Ciliary dysfunction has been shown to Jeune syndrome (ATD) . Ellis-van Crefeld syndrome (EVC) . underlie a broad range of overlapping, clinically and Sensenbrenner syndrome . Primary ciliary dyskinesia genetically heterogeneous phenotypes, collectively (Kartagener syndrome) . von Hippel-Lindau (VHL) . termed ciliopathies. Literally, all organs can be affected. Tuberous sclerosis (TSC) . Oligogenic inheritance . Modifier. Frequent cilia-related manifestations are (poly)cystic Mutational load kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous Introduction system, occurring either isolated or as part of syn- dromes. Characterization of ciliopathies and the decisive Defective cellular organelles such as mitochondria, perox- role of primary cilia in signal transduction and cell isomes, and lysosomes are well-known -
Near-Atomic Structures of the Bbsome Reveal the Basis for Bbsome
RESEARCH ARTICLE Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes Shuang Yang1†, Kriti Bahl2†, Hui-Ting Chou1‡, Jonathan Woodsmith3, Ulrich Stelzl3, Thomas Walz1*, Maxence V Nachury2* 1Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, United States; 2Department of Ophthalmology, University of California San Francisco, San Francisco, United States; 3Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz and BioTechMed-Graz, Graz, Austria Abstract Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the *For correspondence: interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, [email protected] (TW); and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to [email protected] (MVN) be recognized by the BBSome. †These authors contributed equally to this work Present address: ‡Department of Therapeutic Discovery, Amgen Introduction Inc, South San Francisco, United Cilia dynamically concentrate signaling receptors to sense and transduce signals as varied as light, States odorant molecules, Hedgehog morphogens and ligands of G protein-coupled receptors (GPCRs) Competing interests: The (Anvarian et al., 2019; Bangs and Anderson, 2017; Nachury and Mick, 2019). Highlighting the authors declare that no functional importance of dynamic ciliary trafficking, the appropriate transduction of Hedgehog signal competing interests exist. -
Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants. -
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E
www.nature.com/scientificreports OPEN Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E. Hendricks1,2, Elena G. Bochukova3,4, Gaëlle Marenne1, Julia M. Keogh3, Neli Accepted: 10 April 2017 Atanassova3, Rebecca Bounds3, Eleanor Wheeler1, Vanisha Mistry3, Elana Henning3, Published: xx xx xxxx Understanding Society Scientific Group*, Antje Körner5,6, Dawn Muddyman1, Shane McCarthy1, Anke Hinney7, Johannes Hebebrand7, Robert A. Scott8, Claudia Langenberg8, Nick J. Wareham8, Praveen Surendran9, Joanna M. Howson9, Adam S. Butterworth9,10, John Danesh1,9,10, EPIC-CVD Consortium*, Børge G Nordestgaard11,12, Sune F Nielsen11,12, Shoaib Afzal11,12, SofiaPa padia3, SofieAshford 3, Sumedha Garg3, Glenn L. Millhauser13, Rafael I. Palomino13, Alexandra Kwasniewska3, Ioanna Tachmazidou1, Stephen O’Rahilly3, Eleftheria Zeggini1, UK10K Consortium*, Inês Barroso1,3 & I. Sadaf Farooqi3 Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants inBBS1 , BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. -
The Bbsome Assembly Is Spatially Controlled by BBS1 and BBS4 in Human Cells
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.20.000091; this version posted March 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. The BBSome assembly is spatially controlled by BBS1 and BBS4 in human cells Avishek Prasai1, Marketa Schmidt Cernohorska1, Klara Ruppova1, Veronika Niederlova1, Monika Andelova1, Peter Draber1, Ondrej Stepanek1#, Martina Huranova1# 1 Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic # Correspondence to Martina Huranova [email protected] or Ondrej Stepanek [email protected] Laboratory of Adaptive Immunity Institute of Molecular Genetics Czech Academy of Sciences Videnska 1083 14220 Prague Czech Republic 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.20.000091; this version posted March 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Key words: Bardet-Biedl Syndrome, BBSome, assembly, cilium, ciliopathy, protein sorting Abstract Bardet-Biedl Syndrome (BBS) is a pleiotropic ciliopathy caused by dysfunction of primary cilia. Most BBS patients carry mutations in one of eight genes encoding for subunits of a protein complex, BBSome, which mediates the trafficking of ciliary cargoes. Although, the structure of the BBSome has been resolved recently, the mechanism of assembly of this complicated complex in living cells is poorly understood. -
Invited Review: Genetic and Genomic Mouse Models for Livestock Research
Archives Animal Breeding – serving the animal science community for 60 years Arch. Anim. Breed., 61, 87–98, 2018 https://doi.org/10.5194/aab-61-87-2018 Open Access © Author(s) 2018. This work is distributed under the Creative Commons Attribution 4.0 License. Archives Animal Breeding Invited review: Genetic and genomic mouse models for livestock research Danny Arends, Deike Hesse, and Gudrun A. Brockmann Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, 10115 Berlin, Germany Correspondence: Danny Arends ([email protected]) and Gudrun A. Brockmann ([email protected]) Received: 7 December 2017 – Revised: 3 January 2018 – Accepted: 8 January 2018 – Published: 13 February 2018 Abstract. Knowledge about the function and functioning of single or multiple interacting genes is of the utmost significance for understanding the organism as a whole and for accurate livestock improvement through genomic selection. This includes, but is not limited to, understanding the ontogenetic and environmentally driven regula- tion of gene action contributing to simple and complex traits. Genetically modified mice, in which the functions of single genes are annotated; mice with reduced genetic complexity; and simplified structured populations are tools to gain fundamental knowledge of inheritance patterns and whole system genetics and genomics. In this re- view, we briefly describe existing mouse resources and discuss their value for fundamental and applied research in livestock. 1 Introduction the generation of targeted mutations found their way from model animals to livestock species. Through this progress, During the last 10 years, tools for genome analyses model organisms attain a new position in fundamental sci- have developed tremendously. -
High-Throughput Discovery of Novel Developmental Phenotypes
High-throughput discovery of novel developmental phenotypes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Dickinson, M. E., A. M. Flenniken, X. Ji, L. Teboul, M. D. Wong, J. K. White, T. F. Meehan, et al. 2016. “High-throughput discovery of novel developmental phenotypes.” Nature 537 (7621): 508-514. doi:10.1038/nature19356. http://dx.doi.org/10.1038/nature19356. Published Version doi:10.1038/nature19356 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071918 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nature. Manuscript Author Author manuscript; Manuscript Author available in PMC 2017 March 14. Published in final edited form as: Nature. 2016 September 22; 537(7621): 508–514. doi:10.1038/nature19356. High-throughput discovery of novel developmental phenotypes A full list of authors and affiliations appears at the end of the article. Abstract Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms #Corresponding author: [email protected]. -
Inhibition of Hedgehog Signaling Suppresses Proliferation And
www.nature.com/scientificreports OPEN Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Received: 21 August 2017 Accepted: 9 March 2018 Autosomal Dominant Polycystic Published: xx xx xxxx Kidney Disease cells Luciane M. Silva1,5, Damon T. Jacobs1,5, Bailey A. Allard1,5, Timothy A. Fields2,5, Madhulika Sharma4,5, Darren P. Wallace3,4,5 & Pamela V. Tran 1,5 Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutation of PKD1 or PKD2, which encode polycystin 1 and 2, respectively. The polycystins localize to primary cilia and the functional loss of the polycystin complex leads to the formation and progressive growth of fuid-flled cysts in the kidney. The pathogenesis of ADPKD is complex and molecular mechanisms connecting ciliary dysfunction to renal cystogenesis are unclear. Primary cilia mediate Hedgehog signaling, which modulates cell proliferation and diferentiation in a tissue-dependent manner. Previously, we showed that Hedgehog signaling was increased in cystic kidneys of several PKD mouse models and that Hedgehog inhibition prevented cyst formation in embryonic PKD mouse kidneys treated with cAMP. Here, we show that in human ADPKD tissue, Hedgehog target and activator, Glioma 1, was elevated and localized to cyst-lining epithelial cells and to interstitial cells, suggesting increased autocrine and paracrine Hedgehog signaling in ADPKD, respectively. Further, Hedgehog inhibitors reduced basal and cAMP-induced proliferation of ADPKD cells and cyst formation in vitro. These data suggest that Hedgehog signaling is increased in human ADPKD and that suppression of Hedgehog signaling can counter cellular processes that promote cyst growth in vitro. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is among the most commonly inherited, life-threatening diseases, afecting 1:500 adults worldwide. -
Near-Atomic Structures of the Bbsome Reveal a Novel Mechanism For
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.29.925610; this version posted January 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 TITLE 2 Near-atomic structures of the BBSome reveal a novel mechanism for 3 transition zone crossing 4 RUNNING TITLE 5 Mechanism of BBSome-mediated transition zone crossing 6 AUTHORS: Kriti Bahl1,†,, Shuang Yang2,†, Hui-Ting Chou2,#, Jonathan Woodsmith3, Ulrich 7 Stelzl3, Thomas Walz2,* and Maxence V. Nachury1,* 8 AFFILIATIONS: 9 1- Department of Ophthalmology, University of California San Francisco, CA 94143, USA 10 2- Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY 11 10065, USA 12 3- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University 13 of Graz and BioTechMed-Graz, Graz, Austria. 14 # Current address: Department of Therapeutic Discovery, Amgen Inc., South San Francisco, 15 CA 94080, USA 16 17 * Correspondence : [email protected], [email protected] 18 † These authors contributed equally to this work and are listed alphabetically. bioRxiv preprint doi: https://doi.org/10.1101/2020.01.29.925610; this version posted January 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 19 ABSTRACT 20 The BBSome is a complex of eight Bardet-Biedl Syndrome (BBS) proteins that removes signaling 21 receptors from cilia. -
Indian Journal for the Practicing Doctor Vol 7 Issue 1
ISSN : 0973-516X IJPD Vol. 7 Issue 1 Vol. 7, Issue 1, Jan- Feb 2012 IInnddiiaann JJoouurrnnaall ffoorr TThhee PPrraaccttiicciinngg DDooccttoorr Editor-in-Chief Saleem-ur-Rehman Executive Editor SM Kadri Electronic Version (full text) www.ijpd.pbworks.com 2 IJPD Vol. 7 Issue 1 INDIAN JOURNAL FOR THE PRACTISING DOCTOR IJPD (An Official Publication of Directorate of Health Services, Kashmir) www.ijpd.pbworks.com Editor in Chief Saleem-ur-Rehman Director Health Services, Kashmir, JK Executive Editor SM Kadri Epidemiologist, Kashmir Province, Directorate of Health Services, Kashmir, JK Assistant Editors Chinmay Shah Associate Professor, Department of Physiology Government Medical College Bhavnagar, Gujarat. India Rehana Kounsar State Surveillance Officer, IDSP/NCD Directorate of Health Services, Kashmir, JK Jehangir Bakshi Member Secretary, K-RICH (Kashmir Reforms and Innovations Committee for Healthcare) Directorate of Health Services, Kashmir, JK National Advisory Board Muzaffar Ahmed Anmol Gupta Member National Disaster Management Professor, Department of Community Medicine, Authority,New Delhi, India IGMC, Shimla, India Showkat Zargar Harish Pemde Director, Sheri- Kashmir Institute of Medical Science Professor of Pediatrics, Lady Hardinge Medical (SKIMS) , Srinagar , JK College, Kalawati Saran Children's Hospital, Delhi. Qazi Masood Ahmed D. Thamma Rao Principal, Government Medical College Senior Advisor, Public Health Foundation of India Srinagar, JK New Delhi Abdul Hamid Zargar Yogeshwar Gupta Member Institute Body, AIIMS, Specialist in Hospital and Health Care Management, Chairman, Independent Ethics Committee JK Fortis- Escorts Hospital & Research Centre, New Delhi Kanav Kahol Parvez Koul Team Leader, Division of Affordable Head, Department of Medicine Health Technologies, PHFI, Sheri- Kashmir Institute of Medical Science New Delhi, India (SKIMS) Srinagar, JK Tarun Seem Masood Tanvir IRS, Addl. -
Essential Genes and Their Role in Autism Spectrum Disorder
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality. -
Loss of C. Elegans BBS-7 and BBS-8 Protein Function Results in Cilia Defects and Compromised Intraflagellar Transport
Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport Oliver E. Blacque,1 Michael J. Reardon,2 Chunmei Li,1 Jonathan McCarthy,1 Moe R. Mahjoub,3 Stephen J. Ansley,4 Jose L. Badano,4 Allan K. Mah,1 Philip L. Beales,6 William S. Davidson,1 Robert C. Johnsen,1 Mark Audeh,2 Ronald H.A. Plasterk,7 David L. Baillie,1 Nicholas Katsanis,4,5 Lynne M. Quarmby,3 Stephen R. Wicks,2 and Michel R. Leroux1,8 1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada; 2Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, USA; 3Department of Biological Sciences, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada; 4Institute of Genetic Medicine and 5Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland 21287, USA; 6Molecular Medicine Unit, Institute of Child Health, University College London, London WC1 1EH, UK; 7The Hubrecht Laboratory, Netherlands Institute of Developmental Biology, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands Bardet-Biedl syndrome (BBS) is a genetically heterogeneous developmental disorder whose molecular basis is largely unknown. Here, we show that mutations in the Caenorhabditis elegans bbs-7 and bbs-8 genes cause structural and functional defects in cilia. C. elegans BBS proteins localize predominantly at the base of cilia, and like proteins involved in intraflagellar transport (IFT), a process necessary for cilia biogenesis and maintenance, move bidirectionally along the ciliary axoneme. Importantly, we demonstrate that BBS-7 and BBS-8 are required for the normal localization/motility of the IFT proteins OSM-5/Polaris and CHE-11, and to a notably lesser extent, CHE-2.