1. A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium
- Author
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Tania Attié-Bitach, Sophie Saunier, Mandy Kwong, Nadia Elkhartoufi, Enza Maria Valente, Isabelle Perrault, Joseph G. Gleeson, Alessia Micalizzi, Stéphanie Le Corre, Marta Romani, Julie Litzler, Lydie Burglen, Iain A. Drummond, Kevin J. Wright, Avinash Abhyankar, Julien Saada, Jean-Laurent Casanova, Stanislas Lyonnet, Nathalie Boddaert, Nicolas Chassaing, Arnold Munnich, Jeanne Amiel, Peter K. Jackson, Emilie Filhol, Michel Vekemans, Ferechté Encha-Ravazi, Wolfgang Baehr, Sophie Thomas, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Genentech, Inc., Genentech, Inc. [San Francisco], Massachusetts General Hospital [Boston], Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Universita degli Studi di Messina, Rockefeller University [New York], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], Génétique Humaine des Maladies Infectieuses (Inserm U980), Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Utah, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Howard Hughes Medical Institute (HHMI), University of California [San Diego] (UC San Diego), University of California, and Harvard Medical School [Boston] (HMS)
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Male ,Models, Molecular ,Proteomics ,MESH: Sequence Analysis, DNA ,MESH: Cilia / metabolism ,MESH: Cerebellar Diseases / genetics ,Mutant ,INPP5E ,Ciliopathies ,MESH: Phosphoric Monoester Hydrolases / metabolism ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Cerebellum ,MESH: Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics ,Exome ,MESH: Animals ,Eye Abnormalities ,Genetics (clinical) ,Exome sequencing ,Zebrafish ,Genetics ,0303 health sciences ,MESH: Exome ,MESH: Protein Prenylation ,Splice site mutation ,ADP-Ribosylation Factors ,MESH: ADP-Ribosylation Factors / metabolism ,Cilium ,MESH: Proteomics ,Homozygote ,MESH: Genetic Predisposition to Disease ,MESH: Kidney Diseases, Cystic / genetics ,prenylation ,Kidney Diseases, Cystic ,Pedigree ,Female ,MESH: Models, Molecular ,MESH: Homozygote ,MESH: Abnormalities, Multiple ,MESH: Zebrafish Proteins / metabolism ,PDE6D ,MESH: Pedigree ,Protein Prenylation ,Biology ,MESH: Retina / metabolism ,MESH: Zebrafish / abnormalities ,Joubert syndrome ,Article ,Retina ,MESH: Zebrafish / genetics ,03 medical and health sciences ,MESH: Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism ,primary cilia ,MESH: Cerebellar Diseases / metabolism ,Cerebellar Diseases ,medicine ,Animals ,Humans ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,MESH: Retina / abnormalities ,MESH: Eye Abnormalities / metabolism ,Cilia ,030304 developmental biology ,Cyclic Nucleotide Phosphodiesterases, Type 6 ,MESH: Humans ,Sequence Analysis, DNA ,Zebrafish Proteins ,medicine.disease ,MESH: Cerebellum / abnormalities ,Phosphoric Monoester Hydrolases ,MESH: Male ,MESH: Phosphoric Monoester Hydrolases / genetics ,MESH: Eye Abnormalities / genetics ,Protein prenylation ,MESH: Zebrafish Proteins / genetics ,MESH: Female ,030217 neurology & neurosurgery ,MESH: Kidney Diseases, Cystic / metabolism - Abstract
International audience; 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.
- Published
- 2014