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  1. AU="Oliver E Blacque"
  2. AU="Gontijo, Daniel Lopes"
  3. AU="Koch, P"
  4. AU="Shimul Chowdhury"
  5. AU="Hall, Peter E"
  6. AU="Obraztsov, Petr A"
  7. AU="Santacaterina, Fabio"
  8. AU="Rosales, M E"
  9. AU=Kallmes D F
  10. AU="Ge, Xiaomeng"
  11. AU="Michaloliakos, I"
  12. AU="Rayce, Signe Boe"
  13. AU="Heiman Joel"
  14. AU=Rashedi Jalil
  15. AU="Rodríguez-Tovar, Aída Verónica"

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  1. Artikel ; Online: Interpreting the pathogenicity of Joubert syndrome missense variants in Caenorhabditis elegans

    Karen I. Lange / Sofia Tsiropoulou / Katarzyna Kucharska / Oliver E. Blacque

    Disease Models & Mechanisms, Vol 14, Iss

    2021  Band 1

    Abstract: Ciliopathies are inherited disorders caused by defects in motile and non-motile (primary) cilia. Ciliopathy syndromes and associated gene variants are often highly pleiotropic and represent exemplars for interrogating genotype-phenotype correlations. ... ...

    Abstract Ciliopathies are inherited disorders caused by defects in motile and non-motile (primary) cilia. Ciliopathy syndromes and associated gene variants are often highly pleiotropic and represent exemplars for interrogating genotype-phenotype correlations. Towards understanding disease mechanisms in the context of ciliopathy mutations, we have used a leading model organism for cilia and ciliopathy research, Caenorhabditis elegans, together with gene editing, to characterise two missense variants (P74S and G155S) in mksr-2/B9D2 associated with Joubert syndrome (JBTS). B9D2 functions within the Meckel syndrome (MKS) module at the ciliary base transition zone (TZ) compartment and regulates the molecular composition and sensory/signalling functions of the cilium. Quantitative assays of cilium/TZ structure and function, together with knock-in reporters, confirm that both variant alleles are pathogenic in worms. G155S causes a more severe overall phenotype and disrupts endogenous MKSR-2 organisation at the TZ. Recapitulation of the patient biallelic genotype shows that compound heterozygous worms phenocopy worms homozygous for P74S. The P74S and G155S alleles also reveal evidence of a very close functional association between the B9D2-associated B9 complex and MKS-2/TMEM216. Together, these data establish C. elegans as a model for interpreting JBTS mutations and provide further insight into MKS module organisation. This article has an associated First Person interview with the first author of the paper.
    Schlagwörter b9d2 ; c. elegans ; joubert syndrome ; cilia ; mksr-2 ; transition zone ; Medicine ; R ; Pathology ; RB1-214
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2021-01-01T00:00:00Z
    Verlag The Company of Biologists
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: ERICH3 in Primary Cilia Regulates Cilium Formation and the Localisations of Ciliary Transport and Sonic Hedgehog Signaling Proteins

    Mona Alsolami / Stefanie Kuhns / Manal Alsulami / Oliver E. Blacque

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Band 13

    Abstract: Abstract Intraflagellar transport (IFT) is essential for the formation and function of the microtubule-based primary cilium, which acts as a sensory and signalling device at the cell surface. Consisting of IFT-A/B and BBSome cargo adaptors that associate ...

    Abstract Abstract Intraflagellar transport (IFT) is essential for the formation and function of the microtubule-based primary cilium, which acts as a sensory and signalling device at the cell surface. Consisting of IFT-A/B and BBSome cargo adaptors that associate with molecular motors, IFT transports protein into (anterograde IFT) and out of (retrograde IFT) the cilium. In this study, we identify the mostly uncharacterised ERICH3 protein as a component of the mammalian primary cilium. Loss of ERICH3 causes abnormally short cilia and results in the accumulation of IFT-A/B proteins at the ciliary tip, together with reduced ciliary levels of retrograde transport regulators, ARL13B, INPP5E and BBS5. We also show that ERICH3 ciliary localisations require ARL13B and BBSome components. Finally, ERICH3 loss causes positive (Smoothened) and negative (GPR161) regulators of sonic hedgehog signaling (Shh) to accumulate at abnormally high levels in the cilia of pathway-stimulated cells. Together, these findings identify ERICH3 as a novel component of the primary cilium that regulates cilium length and the ciliary levels of Shh signaling molecules. We propose that ERICH3 functions within retrograde IFT-associated pathways to remove signaling proteins from cilia.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 571
    Sprache Englisch
    Erscheinungsdatum 2019-11-01T00:00:00Z
    Verlag Nature Publishing Group
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: Genetic Deletion of Zebrafish Rab28 Causes Defective Outer Segment Shedding, but Not Retinal Degeneration

    Stephen P. Carter / Ailís L. Moran / David Matallanas / Gavin J. McManus / Oliver E. Blacque / Breandán N. Kennedy

    Frontiers in Cell and Developmental Biology, Vol

    2020  Band 8

    Abstract: The photoreceptor outer segment is the canonical example of a modified and highly specialized cilium, with an expanded membrane surface area in the form of disks or lamellae for efficient light detection. Many ciliary proteins are essential for normal ... ...

    Abstract The photoreceptor outer segment is the canonical example of a modified and highly specialized cilium, with an expanded membrane surface area in the form of disks or lamellae for efficient light detection. Many ciliary proteins are essential for normal photoreceptor function and cilium dysfunction often results in retinal degeneration leading to impaired vision. Herein, we investigate the function and localization of the ciliary G-protein RAB28 in zebrafish cone photoreceptors. CRISPR-Cas9 generated rab28 mutant zebrafish display significantly reduced shed outer segment material/phagosomes in the RPE at 1 month post fertilization (mpf), but otherwise normal visual function up to 21 dpf and retinal structure up to 12 mpf. Cone photoreceptor-specific transgenic reporter lines show Rab28 localizes almost exclusively to outer segments, independently of GTP/GDP nucleotide binding. Co-immunoprecipitation analysis demonstrates tagged Rab28 interacts with components of the phototransduction cascade, including opsins, phosphodiesterase 6C and guanylate cyclase 2D. Our data shed light on RAB28 function in cones and provide a model for RAB28-associated cone-rod dystrophy.
    Schlagwörter zebrafish ; cilia ; retinal degeneration ; visual function ; photoreceptor ; small G protein ; Biology (General) ; QH301-705.5
    Sprache Englisch
    Erscheinungsdatum 2020-03-01T00:00:00Z
    Verlag Frontiers Media S.A.
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Ciliary Rab28 and the BBSome negatively regulate extracellular vesicle shedding

    Jyothi S Akella / Stephen P Carter / Ken Nguyen / Sofia Tsiropoulou / Ailis L Moran / Malan Silva / Fatima Rizvi / Breandan N Kennedy / David H Hall / Maureen M Barr / Oliver E Blacque

    eLife, Vol

    2020  Band 9

    Abstract: Cilia both receive and send information, the latter in the form of extracellular vesicles (EVs). EVs are nano-communication devices that influence cell, tissue, and organism behavior. Mechanisms driving ciliary EV biogenesis are almost entirely unknown. ... ...

    Abstract Cilia both receive and send information, the latter in the form of extracellular vesicles (EVs). EVs are nano-communication devices that influence cell, tissue, and organism behavior. Mechanisms driving ciliary EV biogenesis are almost entirely unknown. Here, we show that the ciliary G-protein Rab28, associated with human autosomal recessive cone-rod dystrophy, negatively regulates EV levels in the sensory organs of Caenorhabditis elegans in a cilia specific manner. Sequential targeting of lipidated Rab28 to periciliary and ciliary membranes is highly dependent on the BBSome and the prenyl-binding protein phosphodiesterase 6 subunit delta (PDE6D), respectively, and BBSome loss causes excessive and ectopic EV production. We also find that EV defective mutants display abnormalities in sensory compartment morphogenesis. Together, these findings reveal that Rab28 and the BBSome are key in vivo regulators of EV production at the periciliary membrane and suggest that EVs may mediate signaling between cilia and glia to shape sensory organ compartments. Our data also suggest that defects in the biogenesis of cilia-related EVs may contribute to human ciliopathies.
    Schlagwörter cilia ; Rab28 ; PKD2 ; extracellular vesicles ; BBSome ; ciliopathy ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 571
    Sprache Englisch
    Erscheinungsdatum 2020-02-01T00:00:00Z
    Verlag eLife Sciences Publications Ltd
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: Environmental responsiveness of tubulin glutamylation in sensory cilia is regulated by the p38 MAPK pathway

    Yoshishige Kimura / Koji Tsutsumi / Alu Konno / Koji Ikegami / Saira Hameed / Tomomi Kaneko / Oktay Ismail Kaplan / Takayuki Teramoto / Manabi Fujiwara / Takeshi Ishihara / Oliver E. Blacque / Mitsutoshi Setou

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Band 13

    Abstract: Abstract Glutamylation is a post-translational modification found on tubulin that can alter the interaction between microtubules (MTs) and associated proteins. The molecular mechanisms regulating tubulin glutamylation in response to the environment are ... ...

    Abstract Abstract Glutamylation is a post-translational modification found on tubulin that can alter the interaction between microtubules (MTs) and associated proteins. The molecular mechanisms regulating tubulin glutamylation in response to the environment are not well understood. Here, we show that in the sensory cilia of Caenorhabditis elegans, tubulin glutamylation is upregulated in response to various signals such as temperature, osmolality, and dietary conditions. Similarly, tubulin glutamylation is modified in mammalian photoreceptor cells following light adaptation. A tubulin glutamate ligase gene ttll-4, which is essential for tubulin glutamylation of axonemal MTs in sensory cilia, is activated by p38 MAPK. Amino acid substitution of TTLL-4 has revealed that a Thr residue (a putative MAPK-phosphorylation site) is required for enhancement of tubulin glutamylation. Intraflagellar transport (IFT), a bidirectional trafficking system specifically observed along axonemal MTs, is required for the formation, maintenance, and function of sensory cilia. Measurement of the velocity of IFT particles revealed that starvation accelerates IFT, which was also dependent on the Thr residue of TTLL-4. Similarly, starvation-induced attenuation of avoidance behaviour from high osmolality conditions was also dependent on ttll-4. Our data suggest that a novel evolutionarily conserved regulatory system exists for tubulin glutamylation in sensory cilia in response to the environment.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 612
    Sprache Englisch
    Erscheinungsdatum 2018-05-01T00:00:00Z
    Verlag Nature Publishing Group
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    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: EFHC1, implicated in juvenile myoclonic epilepsy, functions at the cilium and synapse to modulate dopamine signaling

    Catrina M Loucks / Kwangjin Park / Denise S Walker / Andrea H McEwan / Tiffany A Timbers / Evan L Ardiel / Laura J Grundy / Chunmei Li / Jacque-Lynne Johnson / Julie Kennedy / Oliver E Blacque / William Schafer / Catharine H Rankin / Michel R Leroux

    eLife, Vol

    2019  Band 8

    Abstract: Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied ...

    Abstract Neurons throughout the mammalian brain possess non-motile cilia, organelles with varied functions in sensory physiology and cellular signaling. Yet, the roles of cilia in these neurons are poorly understood. To shed light into their functions, we studied EFHC1, an evolutionarily conserved protein required for motile cilia function and linked to a common form of inherited epilepsy in humans, juvenile myoclonic epilepsy (JME). We demonstrate that C. elegans EFHC-1 functions within specialized non-motile mechanosensory cilia, where it regulates neuronal activation and dopamine signaling. EFHC-1 also localizes at the synapse, where it further modulates dopamine signaling in cooperation with the orthologue of an R-type voltage-gated calcium channel. Our findings unveil a previously undescribed dual-regulation of neuronal excitability at sites of neuronal sensory input (cilium) and neuronal output (synapse). Such a distributed regulatory mechanism may be essential for establishing neuronal activation thresholds under physiological conditions, and when impaired, may represent a novel pathomechanism for epilepsy.
    Schlagwörter EFHC1 ; juvenile myoclonic epilepsy ; cilia ; synapse ; Caenorhabditis elegans ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 571
    Sprache Englisch
    Erscheinungsdatum 2019-02-01T00:00:00Z
    Verlag eLife Sciences Publications Ltd
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

    Paul W. Chrystal / Nils J. Lambacher / Lance P. Doucette / James Bellingham / Elena R. Schiff / Nicole C. L. Noel / Chunmei Li / Sofia Tsiropoulou / Geoffrey A. Casey / Yi Zhai / Nathan J. Nadolski / Mohammed H. Majumder / Julia Tagoe / Fabiana D’Esposito / Maria Francesca Cordeiro / Susan Downes / Jill Clayton-Smith / Jamie Ellingford / Genomics England Research Consortium /
    Omar A. Mahroo / Jennifer C. Hocking / Michael E. Cheetham / Andrew R. Webster / Gert Jansen / Oliver E. Blacque / W. Ted Allison / Ping Yee Billie Au / Ian M. MacDonald / Gavin Arno / Michel R. Leroux

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Band 22

    Abstract: Motile and non-motile cilia have distinct functions and protein complexes associated with them. Here, the authors show the conserved protein CFAP20 is important for both motile and non-motile cilia and is distinct from other ciliopathy-associated domains ...

    Abstract Motile and non-motile cilia have distinct functions and protein complexes associated with them. Here, the authors show the conserved protein CFAP20 is important for both motile and non-motile cilia and is distinct from other ciliopathy-associated domains or macromolecular complexes.
    Schlagwörter Science ; Q
    Sprache Englisch
    Erscheinungsdatum 2022-11-01T00:00:00Z
    Verlag Nature Portfolio
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  8. Artikel ; Online: MISC-1/OGC links mitochondrial metabolism, apoptosis and insulin secretion.

    Marco Gallo / Donha Park / Dan S Luciani / Katarzyna Kida / Ferdinando Palmieri / Oliver E Blacque / James D Johnson / Donald L Riddle

    PLoS ONE, Vol 6, Iss 3, p e

    2011  Band 17827

    Abstract: We identified MISC-1 (Mitochondrial Solute Carrier) as the C. elegans orthologue of mammalian OGC (2-oxoglutarate carrier). OGC was originally identified for its ability to transfer α-ketoglutarate across the inner mitochondrial membrane. However, we ... ...

    Abstract We identified MISC-1 (Mitochondrial Solute Carrier) as the C. elegans orthologue of mammalian OGC (2-oxoglutarate carrier). OGC was originally identified for its ability to transfer α-ketoglutarate across the inner mitochondrial membrane. However, we found that MISC-1 and OGC are not solely involved in metabolic control. Our data show that these orthologous proteins participate in phylogenetically conserved cellular processes, like control of mitochondrial morphology and induction of apoptosis. We show that MISC-1/OGC is required for proper mitochondrial fusion and fission events in both C. elegans and human cells. Transmission electron microscopy reveals that loss of MISC-1 results in a decreased number of mitochondrial cristae, which have a blebbed appearance. Furthermore, our pull-down experiments show that MISC-1 and OGC interact with the anti-apoptotic proteins CED-9 and Bcl-x(L), respectively, and with the pro-apoptotic protein ANT. Knock-down of misc-1 in C. elegans and OGC in mouse cells induces apoptosis through the caspase cascade. Genetic analysis suggests that MISC-1 controls apoptosis through the physiological pathway mediated by the LIN-35/Rb-like protein. We provide genetic and molecular evidence that absence of MISC-1 increases insulin secretion and enhances germline stem cell proliferation in C. elegans. Our study suggests that the mitochondrial metabolic protein MISC-1/OGC integrates metabolic, apoptotic and insulin secretion functions. We propose a novel mechanism by which mitochondria integrate metabolic and cell survival signals. Our data suggest that MISC-1/OGC functions by sensing the metabolic status of mitochondria and directly activate the apoptotic program when required. Our results suggest that controlling MISC-1/OGC function allows regulation of mitochondrial morphology and cell survival decisions by the metabolic needs of the cell.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2011-03-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
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  9. Artikel ; Online: MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.

    Chunmei Li / Victor L Jensen / Kwangjin Park / Julie Kennedy / Francesc R Garcia-Gonzalo / Marta Romani / Roberta De Mori / Ange-Line Bruel / Dominique Gaillard / Bérénice Doray / Estelle Lopez / Jean-Baptiste Rivière / Laurence Faivre / Christel Thauvin-Robinet / Jeremy F Reiter / Oliver E Blacque / Enza Maria Valente / Michel R Leroux

    PLoS Biology, Vol 14, Iss 3, p e

    2016  Band 1002416

    Abstract: Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] ... ...

    Abstract Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module-associated proteins--including the previously uncharacterised mammalian Tmem80--and ...
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 570
    Sprache Englisch
    Erscheinungsdatum 2016-03-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
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    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  10. Artikel ; Online: CiliaCarta

    Teunis J P van Dam / Julie Kennedy / Robin van der Lee / Erik de Vrieze / Kirsten A Wunderlich / Suzanne Rix / Gerard W Dougherty / Nils J Lambacher / Chunmei Li / Victor L Jensen / Michel R Leroux / Rim Hjeij / Nicola Horn / Yves Texier / Yasmin Wissinger / Jeroen van Reeuwijk / Gabrielle Wheway / Barbara Knapp / Jan F Scheel /
    Brunella Franco / Dorus A Mans / Erwin van Wijk / François Képès / Gisela G Slaats / Grischa Toedt / Hannie Kremer / Heymut Omran / Katarzyna Szymanska / Konstantinos Koutroumpas / Marius Ueffing / Thanh-Minh T Nguyen / Stef J F Letteboer / Machteld M Oud / Sylvia E C van Beersum / Miriam Schmidts / Philip L Beales / Qianhao Lu / Rachel H Giles / Radek Szklarczyk / Robert B Russell / Toby J Gibson / Colin A Johnson / Oliver E Blacque / Uwe Wolfrum / Karsten Boldt / Ronald Roepman / Victor Hernandez-Hernandez / Martijn A Huynen

    PLoS ONE, Vol 14, Iss 5, p e

    An integrated and validated compendium of ciliary genes.

    2019  Band 0216705

    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 ... ...

    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/.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2019-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
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