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A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium

Authors

  • Sophie Thomas,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
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    • These authors contributed equally to this work.

  • Kevin J. Wright,

    1. Genentech Inc, South San Francisco, California
    Current affiliation:
    1. Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, California
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    • These authors contributed equally to this work.

  • Stéphanie Le Corre,

    1. Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts
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  • Alessia Micalizzi,

    1. Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico «Casa Sollievo della Sofferenza » San Giovanni Rotondo, Italy
    2. Department of Medical and Surgical Paediatric Sciences, University of Messina, Messina, Italy
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  • Marta Romani,

    1. Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico «Casa Sollievo della Sofferenza » San Giovanni Rotondo, Italy
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  • Avinash Abhyankar,

    1. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York
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  • Julien Saada,

    1. Service de Gynécologie obstétrique, Hôpital Antoine-Béclère, Assistance Publique – Hôpitaux de Paris (AP-HP), Clamart, France
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  • Isabelle Perrault,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
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  • Jeanne Amiel,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    3. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Julie Litzler,

    1. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Emilie Filhol,

    1. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    2. INSERM U983, Hôpital Necker-Enfants Malades, Paris, France
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  • Nadia Elkhartoufi,

    1. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Mandy Kwong,

    1. Genentech Inc, South San Francisco, California
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  • Jean-Laurent Casanova,

    1. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    2. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York
    3. Laboratory of Human Genetics of Infectious Diseases INSERM U980, Necker Medical School, Paris, France
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  • Nathalie Boddaert,

    1. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    2. Service de radiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Wolfgang Baehr,

    1. University of Utah Health Science Center, Salt Lake City
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  • Stanislas Lyonnet,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    3. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Arnold Munnich,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    3. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Lydie Burglen,

    1. AP-HP, Hôpital Trousseau, Centre de référence des malformations et maladies congénitales du cervelet et Service de génétique, Paris, France
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  • Nicolas Chassaing,

    1. Service de génétique médicale, CHU de Toulouse; EA-4555 UPSIII, Toulouse, France
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  • Ferechté Encha-Ravazi,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    3. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Michel Vekemans,

    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    3. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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  • Joseph G. Gleeson,

    1. Neurogenetics Laboratory, Institute for Genomic Medicine, Department of Neurosciences and Pediatrics, Howard Hughes Medical Institute, University of California, San Diego, California
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  • Enza Maria Valente,

    1. Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico «Casa Sollievo della Sofferenza » San Giovanni Rotondo, Italy
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  • Peter K. Jackson,

    1. Genentech Inc, South San Francisco, California
    Current affiliation:
    1. Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, California
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  • Iain A. Drummond,

    1. Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts
    2. Department of Genetics, Harvard Medical School, Boston, Massachusetts
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  • Sophie Saunier,

    1. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    2. INSERM U983, Hôpital Necker-Enfants Malades, Paris, France
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    • These authors contributed equally to this work.

  • Tania Attié-Bitach

    Corresponding author
    1. INSERM U781, Hôpital Necker-Enfants Malades, Paris, France
    2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France
    3. Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
    • Corresponding to: Tania Attie-Bitach, Département de Génétique et INSERM U-781, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: tania.attie@inserm.fr

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    • These authors contributed equally to this work.


  • Contract grant sponsors: Agence Nationale de la Recherche (ANR 1122 01 FOETOCILPATH); IMAGINE Institute; Fondation pour la Recherche Médicale (FRM DEQ20071210558); National Institutes of Health (DK053093, DK070263, NS048453); European Research Council (ERC Starting Grant 260888); The Italian Ministry of Health (Ricerca Corrente 2012 and Ricerca Finalizzata Malattie Rare 2008).

  • Communicated by Ming Qi

ABSTRACT

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the « molar tooth sign ». JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.

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