Abstract
The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.
Original language | English |
---|---|
Article number | 0216705 |
Number of pages | 32 |
Journal | PLOS ONE |
Volume | 14 |
Issue number | 5 |
DOIs | |
Publication status | Published - 16 May 2019 |
Keywords
- DIFFERENTIATION
- EXPRESSION
- IDENTIFICATION
- INTRAFLAGELLAR TRANSPORT
- LEBER CONGENITAL AMAUROSIS
- MUTATIONS
- PRIMARY CILIUM
- RETINAL PHOTORECEPTOR CELLS
- SOLUTE-CARRIER-PROTEIN
- TRANSITION ZONE
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- 10.1371/journal.pone.0216705Licence: CC BY
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In: PLOS ONE, Vol. 14, No. 5, 0216705, 16.05.2019.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - CiliaCarta
T2 - An integrated and validated compendium of ciliary genes
AU - van Dam, Teunis J. P.
AU - Kennedy, Julie
AU - van der Lee, Robin
AU - de Vrieze, Erik
AU - Wunderlich, Kirsten A.
AU - Rix, Suzanne
AU - Dougherty, Gerard W.
AU - Lambacher, Nils J.
AU - Li, Chunmei
AU - Jensen, Victor L.
AU - Leroux, Michel R.
AU - Hjeij, Rim
AU - Horn, Nicola
AU - Texier, Yves
AU - Wissinger, Yasmin
AU - van Reeuwijk, Jeroen
AU - Wheway, Gabrielle
AU - Knapp, Barbara
AU - Scheel, Jan F.
AU - Franco, Brunella
AU - Mans, Dorus A.
AU - van Wijk, Erwin
AU - Kepes, Francois
AU - Slaats, Gisela G.
AU - Toedt, Grischa
AU - Kremer, Hannie
AU - Omran, Heymut
AU - Szymanska, Katarzyna
AU - Koutroumpas, Konstantinos
AU - Ueffing, Marius
AU - Nguyen, Thanh-Minh T.
AU - Letteboer, Stef J. F.
AU - Oud, Machteld M.
AU - van Beersum, Sylvia E. C.
AU - Schmidts, Miriam
AU - Beales, Philip L.
AU - Lu, Qianhao
AU - Giles, Rachel H.
AU - Szklarczyk, Radek
AU - Russell, Robert B.
AU - Gibson, Toby J.
AU - Johnson, Colin A.
AU - Blacque, Oliver E.
AU - Wolfrum, Uwe
AU - Boldt, Karsten
AU - Roepman, Ronald
AU - Hernandez-Hernandez, Victor
AU - Huynen, Martijn A.
N1 - Funding Information: This work was supported by the European Community’s Seventh Framework Programme [241955, 278568 to MU and KB, 602273 to RS]; the Virgo consortium, funded by the Dutch government [FES0908 to TvD, RvdL and MAH]; the Netherlands Genomics Initiative [050-060-452 to TvD, RvdL and MAH]; the Canadian Institutes of Health Research [MOP-142243, MOP-82870 and PJT-156042 to MRL]; Michael Smith Foundation for Health Research to MRL and VLJ; Kidney Research Scientist Core Education and National Training fellowship to VLJ; The Foundation Fighting Blindness [PPA-0717-0719-RAD to UW, RR, and MU]; the Dutch Kidney Foundation “KOUNCIL” consortium [CP11.18 to RHG, PLB and RR]; The Deutsche Forschungsgemeinschaft [Excellence grant CellNetworks to RBR and QL, CRC1140 “Kidney Disease – From Genes to Mechanisms” to MS, collaborative research center grant SFB-1411 KIDGEM to MS]; Metakids Foundation to RS; the National Institute for Health Research to PLB and VH-H. PLB is an NIHR Senior Investigator; Radboudumc Hypatia Tenure Track Fellowship, Radboud Universiteit excellence fellowship, ERC starting grant TREATCilia, grant agreement no. 716344 to MS; and the Netherlands Organization for Scientific Research [NWO Vici-865.12.005 to RR]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We kindly acknowledge Prof. Dr. N. Katsanis and J. R. Willer from Duke University USA for providing several of the clone constructs used as baits in the SILAC and Y2H data sets. We also thank the Caenorhabditis elegans Genetics Center (Minnesota, USA), the National Bioresource project (Tokyo, Japan), the International C. elegans gene knockout consortium, and the C. elegans Million Mutation Project for nematode reagents. We thank Emine Bolat, Ideke Lamers, Mon-iek Riemersma, and Karlien Coene for performing yeast two-hybrid and SILAC experiments. Funding Information: InstitutesofHealthResearch[MOP-142243,MOP-82870andPJT-156042toMRL];MichaelSmith FoundationforHealthResearchtoMRLandVLJ; KidneyResearchScientistCoreEducationand NationalTrainingfellowshiptoVLJ;TheFoundation FightingBlindness[PPA-0717-0719-RADtoUW, RR,andMU];theDutchKidneyFoundation “KOUNCIL”consortium[CP11.18toRHG,PLBand RR];TheDeutscheForschungsgemeinschaft [ExcellencegrantCellNetworkstoRBRandQL, CRC1140“KidneyDisease–FromGenesto Mechanisms”toMS,collaborativeresearchcenter grantSFB-1411KIDGEMtoMS];Metakids FoundationtoRS;theNationalInstituteforHealth ResearchtoPLBandVH-H.PLBisanNIHRSenior Investigator;RadboudumcHypatiaTenureTrack Fellowship,RadboudUniversiteitexcellence fellowship,ERCstartinggrantTREATCilia,grant agreementno.716344toMS;andtheNetherlands OrganizationforScientificResearch[NWOVici-865.12.005toRR].Thefundershadnorolein studydesign,datacollectionandanalysis,decision topublish,orpreparationofthemanuscript. Publisher Copyright: © 2019 van Dam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/5/16
Y1 - 2019/5/16
N2 - The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.
AB - The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.
KW - DIFFERENTIATION
KW - EXPRESSION
KW - IDENTIFICATION
KW - INTRAFLAGELLAR TRANSPORT
KW - LEBER CONGENITAL AMAUROSIS
KW - MUTATIONS
KW - PRIMARY CILIUM
KW - RETINAL PHOTORECEPTOR CELLS
KW - SOLUTE-CARRIER-PROTEIN
KW - TRANSITION ZONE
U2 - 10.1371/journal.pone.0216705
DO - 10.1371/journal.pone.0216705
M3 - Article
C2 - 31095607
SN - 1932-6203
VL - 14
JO - PLOS ONE
JF - PLOS ONE
IS - 5
M1 - 0216705
ER -