A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium |
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| Authors: | Sophie Thomas Kevin J Wright Stéphanie Le Corre Alessia Micalizzi Marta Romani Avinash Abhyankar Julien Saada Isabelle Perrault Jeanne Amiel Julie Litzler Emilie Filhol Nadia Elkhartoufi Mandy Kwong Jean‐Laurent Casanova Nathalie Boddaert Wolfgang Baehr Stanislas Lyonnet Arnold Munnich Lydie Burglen Nicolas Chassaing Ferechté Encha‐Ravazi Michel Vekemans Joseph G Gleeson Enza Maria Valente Peter K Jackson Iain A Drummond Sophie Saunier Tania Attié‐Bitach |
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| Institution: | 1. INSERM U781, H?pital Necker‐Enfants Malades, Paris, France;2. Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, France;3. Genentech Inc, South San Francisco, California;4. Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts;5. Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico ?Casa Sollievo della Sofferenza 6. ? San Giovanni Rotondo, Italy;7. Department of Medical and Surgical Paediatric Sciences, University of Messina, Messina, Italy;8. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York;9. Service de Gynécologie obstétrique, H?pital Antoine‐Béclère, Assistance Publique – H?pitaux de Paris (AP‐HP), Clamart, France;10. Département de Génétique, H?pital Necker‐Enfants Malades, AP‐HP, Paris, France;11. INSERM U983, H?pital Necker‐Enfants Malades, Paris, France;12. Laboratory of Human Genetics of Infectious Diseases INSERM U980, Necker Medical School, Paris, France;13. Service de radiologie Pédiatrique, H?pital Necker‐Enfants Malades, AP‐HP, Paris, France;14. University of Utah Health Science Center, Salt Lake City;15. AP‐HP, H?pital Trousseau, Centre de référence des malformations et maladies congénitales du cervelet et Service de génétique, Paris, France;16. Service de génétique médicale, CHU de Toulouse;17. EA‐4555 UPSIII, Toulouse, France;18. Neurogenetics Laboratory, Institute for Genomic Medicine, Department of Neurosciences and Pediatrics, Howard Hughes Medical Institute, University of California, San Diego, California;19. Department of Genetics, Harvard Medical School, Boston, Massachusetts |
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| 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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| Keywords: | Joubert syndrome primary cilia PDE6D INPP5E prenylation |
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