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  1. Article ; Online: The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies.

    Van De Weghe, Julie C / Gomez, Arianna / Doherty, Dan

    Annual review of genomics and human genetics

    2022  Volume 23, Page(s) 301–329

    Abstract: The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions ... ...

    Abstract The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. Primary cilia are near-ubiquitous, microtubule-based organelles that play crucial roles in development and homeostasis. Protruding from the cell, these cellular antennae sense diverse signals and mediate Hedgehog and other critical signaling pathways. Ciliary dysfunction causes many human conditions termed ciliopathies, which range from multiple congenital malformations to adult-onset single-organ failure. Research on the genetics of the JS-MKS-NPH spectrum has spurred extensive functional work exploring the broadly important role of primary cilia in health and disease. This functional work promises to illuminate the mechanisms underlying JS-MKS-NPH in humans, identify therapeutic targets across genetic causes, and generate future precision treatments.
    MeSH term(s) Abnormalities, Multiple/genetics ; Abnormalities, Multiple/metabolism ; Abnormalities, Multiple/pathology ; Cerebellum/abnormalities ; Cerebellum/metabolism ; Cerebellum/pathology ; Child ; Cilia/genetics ; Cilia/metabolism ; Cilia/pathology ; Ciliary Motility Disorders ; Ciliopathies/genetics ; Ciliopathies/metabolism ; Ciliopathies/pathology ; Encephalocele ; Eye Abnormalities/genetics ; Eye Abnormalities/metabolism ; Eye Abnormalities/pathology ; Hedgehog Proteins/metabolism ; Humans ; Kidney Diseases, Cystic ; Polycystic Kidney Diseases/genetics ; Polycystic Kidney Diseases/metabolism ; Polycystic Kidney Diseases/pathology ; Retina/abnormalities ; Retina/metabolism ; Retina/pathology ; Retinitis Pigmentosa
    Chemical Substances Hedgehog Proteins
    Language English
    Publishing date 2022-06-02
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 2037670-4
    ISSN 1545-293X ; 1527-8204
    ISSN (online) 1545-293X
    ISSN 1527-8204
    DOI 10.1146/annurev-genom-121321-093528
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  2. Article ; Online: Protein transport in growing and steady-state cilia.

    Lechtreck, Karl F / Van De Weghe, Julie C / Harris, James Aaron / Liu, Peiwei

    Traffic (Copenhagen, Denmark)

    2017  Volume 18, Issue 5, Page(s) 277–286

    Abstract: Cilia and eukaryotic flagella are threadlike cell extensions with motile and sensory functions. Their assembly requires intraflagellar transport (IFT), a bidirectional motor-driven transport of protein carriers along the axonemal microtubules. IFT moves ... ...

    Abstract Cilia and eukaryotic flagella are threadlike cell extensions with motile and sensory functions. Their assembly requires intraflagellar transport (IFT), a bidirectional motor-driven transport of protein carriers along the axonemal microtubules. IFT moves ample amounts of structural proteins including tubulin into growing cilia likely explaining its critical role for assembly. IFT continues in non-growing cilia contributing to a variety of processes ranging from axonemal maintenance and the export of non-ciliary proteins to cell locomotion and ciliary signaling. Here, we discuss recent data on cues regulating the type, amount and timing of cargo transported by IFT. A regulation of IFT-cargo interactions is critical to establish, maintain and adjust ciliary length, protein composition and function.
    MeSH term(s) Animals ; Cilia/metabolism ; Cilia/physiology ; Flagella/metabolism ; Flagella/physiology ; Humans ; Protein Transport/physiology ; Proteins/metabolism ; Tubulin/metabolism
    Chemical Substances Proteins ; Tubulin
    Language English
    Publishing date 2017-05
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1483852-7
    ISSN 1600-0854 ; 1398-9219
    ISSN (online) 1600-0854
    ISSN 1398-9219
    DOI 10.1111/tra.12474
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  3. Article ; Online: Erratum: Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome.

    Shi, Xiaoyu / Garcia, Galo / Van De Weghe, Julie C / McGorty, Ryan / Pazour, Gregory J / Doherty, Dan / Huang, Bo / Reiter, Jeremy F

    Nature cell biology

    2018  Volume 19, Issue 11, Page(s) 1379

    Abstract: This corrects the article DOI: 10.1038/ncb3599. ...

    Abstract This corrects the article DOI: 10.1038/ncb3599.
    Language English
    Publishing date 2018-02-07
    Publishing country England
    Document type Journal Article ; Published Erratum
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/ncb3622
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  4. Article ; Online: Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome.

    Shi, Xiaoyu / Garcia, Galo / Van De Weghe, Julie C / McGorty, Ryan / Pazour, Gregory J / Doherty, Dan / Huang, Bo / Reiter, Jeremy F

    Nature cell biology

    2017  Volume 19, Issue 10, Page(s) 1178–1188

    Abstract: Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its ... ...

    Abstract Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.
    MeSH term(s) Abnormalities, Multiple/genetics ; Abnormalities, Multiple/metabolism ; Abnormalities, Multiple/pathology ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adolescent ; Adult ; Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Cerebellum/abnormalities ; Cerebellum/metabolism ; Cerebellum/pathology ; Child ; Cilia/metabolism ; Cilia/pathology ; Ciliopathies/genetics ; Ciliopathies/metabolism ; Ciliopathies/pathology ; Eye Abnormalities/genetics ; Eye Abnormalities/metabolism ; Eye Abnormalities/pathology ; Female ; Genetic Predisposition to Disease ; Humans ; Image Processing, Computer-Assisted ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/metabolism ; Kidney Diseases, Cystic/pathology ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice, Inbred C57BL ; Microscopy, Fluorescence/methods ; Mutation ; Patched-1 Receptor/genetics ; Patched-1 Receptor/metabolism ; Phenotype ; Retina/abnormalities ; Retina/metabolism ; Retina/pathology ; Signal Transduction ; Smoothened Receptor/genetics ; Smoothened Receptor/metabolism ; Stochastic Processes ; Young Adult
    Chemical Substances Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Ftm protein, mouse ; Membrane Proteins ; NPHP1 protein, human ; Nphp1 protein, mouse ; Patched-1 Receptor ; Ptch1 protein, mouse ; RPGRIP1L protein, human ; Smo protein, mouse ; Smoothened Receptor ; TCTN2 protein, human
    Language English
    Publishing date 2017-08-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/ncb3599
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes.

    Van De Weghe, Julie C / Giordano, Jessica L / Mathijssen, Inge B / Mojarrad, Majid / Lugtenberg, Dorien / Miller, Caitlin V / Dempsey, Jennifer C / Mohajeri, Mahsa Sadat Asl / van Leeuwen, Elizabeth / Pajkrt, Eva / Klaver, Caroline C W / Houlden, Henry / Eslahi, Atieh / Waters, Aoife M / Bamshad, Michael J / Nickerson, Deborah A / Aggarwal, Vimla S / de Vries, Bert B A / Maroofian, Reza /
    Doherty, Dan

    HGG advances

    2020  Volume 2, Issue 1

    Abstract: The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, ... ...

    Abstract The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense
    Language English
    Publishing date 2020-11-21
    Publishing country United States
    Document type Journal Article
    ISSN 2666-2477
    ISSN (online) 2666-2477
    DOI 10.1016/j.xhgg.2020.100016
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  6. Article ; Online: Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome.

    Latour, Brooke L / Van De Weghe, Julie C / Rusterholz, Tamara Ds / Letteboer, Stef Jf / Gomez, Arianna / Shaheen, Ranad / Gesemann, Matthias / Karamzade, Arezou / Asadollahi, Mostafa / Barroso-Gil, Miguel / Chitre, Manali / Grout, Megan E / van Reeuwijk, Jeroen / van Beersum, Sylvia Ec / Miller, Caitlin V / Dempsey, Jennifer C / Morsy, Heba / Bamshad, Michael J / Nickerson, Deborah A /
    Neuhauss, Stephan Cf / Boldt, Karsten / Ueffing, Marius / Keramatipour, Mohammad / Sayer, John A / Alkuraya, Fowzan S / Bachmann-Gagescu, Ruxandra / Roepman, Ronald / Doherty, Dan

    The Journal of clinical investigation

    2020  Volume 130, Issue 8, Page(s) 4423–4439

    Abstract: Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy characterized by a pathognomonic hindbrain malformation. All known JBTS genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles ... ...

    Abstract Joubert syndrome (JBTS) is a recessive neurodevelopmental ciliopathy characterized by a pathognomonic hindbrain malformation. All known JBTS genes encode proteins involved in the structure or function of primary cilia, ubiquitous antenna-like organelles essential for cellular signal transduction. Here, we used the recently identified JBTS-associated protein armadillo repeat motif-containing 9 (ARMC9) in tandem-affinity purification and yeast 2-hybrid screens to identify a ciliary module whose dysfunction underlies JBTS. In addition to the known JBTS-associated proteins CEP104 and CSPP1, we identified coiled-coil domain containing 66 (CCDC66) and TOG array regulator of axonemal microtubules 1 (TOGARAM1) as ARMC9 interaction partners. We found that TOGARAM1 variants cause JBTS and disrupt TOGARAM1 interaction with ARMC9. Using a combination of protein interaction analyses, characterization of patient-derived fibroblasts, and analysis of CRISPR/Cas9-engineered zebrafish and hTERT-RPE1 cells, we demonstrated that dysfunction of ARMC9 or TOGARAM1 resulted in short cilia with decreased axonemal acetylation and polyglutamylation, but relatively intact transition zone function. Aberrant serum-induced ciliary resorption and cold-induced depolymerization in ARMC9 and TOGARAM1 patient cell lines suggest a role for this new JBTS-associated protein module in ciliary stability.
    MeSH term(s) Abnormalities, Multiple/genetics ; Abnormalities, Multiple/metabolism ; Acetylation ; Animals ; Armadillo Domain Proteins/genetics ; Armadillo Domain Proteins/metabolism ; CRISPR-Cas Systems ; Cerebellum/abnormalities ; Cerebellum/metabolism ; Cilia/genetics ; Cilia/metabolism ; Disease Models, Animal ; Eye Abnormalities/genetics ; Eye Abnormalities/metabolism ; Humans ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/metabolism ; Peptides/genetics ; Peptides/metabolism ; Retina/abnormalities ; Retina/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances ARMC9 protein, zebrafish ; Armadillo Domain Proteins ; Peptides ; Zebrafish Proteins ; polyglutamine (26700-71-0)
    Language English
    Publishing date 2020-05-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI131656
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  7. Article ; Online: Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.

    Van De Weghe, Julie C / Rusterholz, Tamara D S / Latour, Brooke / Grout, Megan E / Aldinger, Kimberly A / Shaheen, Ranad / Dempsey, Jennifer C / Maddirevula, Sateesh / Cheng, Yong-Han H / Phelps, Ian G / Gesemann, Matthias / Goel, Himanshu / Birk, Ohad S / Alanzi, Talal / Rawashdeh, Rifaat / Khan, Arif O / Bamshad, Michael J / Nickerson, Deborah A / Neuhauss, Stephan C F /
    Dobyns, William B / Alkuraya, Fowzan S / Roepman, Ronald / Bachmann-Gagescu, Ruxandra / Doherty, Dan

    American journal of human genetics

    2017  Volume 101, Issue 1, Page(s) 23–36

    Abstract: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. ...

    Abstract Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.
    MeSH term(s) Abnormalities, Multiple/genetics ; Abnormalities, Multiple/pathology ; Animals ; Armadillo Domain Proteins/genetics ; Armadillo Domain Proteins/metabolism ; Basal Bodies/metabolism ; Base Sequence ; Brain/pathology ; Cerebellum/abnormalities ; Cerebellum/pathology ; Cilia/metabolism ; Ciliopathies/genetics ; Ciliopathies/pathology ; Diagnostic Imaging ; Exome/genetics ; Eye Abnormalities/genetics ; Eye Abnormalities/pathology ; Genetic Predisposition to Disease ; Humans ; Kidney Diseases, Cystic/genetics ; Kidney Diseases, Cystic/pathology ; Mutation/genetics ; Phenotype ; Retina/abnormalities ; Retina/pathology ; Sequence Analysis, DNA ; Up-Regulation/genetics ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances ARMC9 protein, human ; ARMC9 protein, zebrafish ; Armadillo Domain Proteins ; Zebrafish Proteins
    Language English
    Publishing date 2017-06-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2017.05.010
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