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

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 ChassaingFerechté Encha-Ravazi, Michel Vekemans, Joseph G. Gleeson, Enza Maria Valente, Peter K. Jackson, Iain A. Drummond, Sophie Saunier, Tania Attié-Bitach

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)137-146
Number of pages10
JournalHuman Mutation
Issue number1
Publication statusPublished - Jan 2014


  • INPP5E
  • Joubert syndrome
  • PDE6D
  • Prenylation
  • Primary cilia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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