title: A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium.
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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wright
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Corre
authors.forename: Alessia
authors.initials: A
authors.lastname: Micalizzi
authors.forename: Marta
authors.initials: M
authors.lastname: Romani
authors.forename: Avinash
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authors.lastname: Abhyankar
authors.forename: Julien
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authors.lastname: Saada
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Julie
authors.initials: J
authors.lastname: Litzler
authors.forename: Emilie
authors.initials: E
authors.lastname: Filhol
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhartoufi
authors.forename: Mandy
authors.initials: M
authors.lastname: Kwong
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Ferechté
authors.initials: F
authors.lastname: Encha-Ravazi
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000015:Abnormalities, Multiple; D000818:Animals; D002526:Cerebellar Diseases / Q000235:genetics* / Q000378:metabolism*; D002531:Cerebellum / Q000002:abnormalities; D002923:Cilia / Q000378:metabolism*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics* / Q000378:metabolism*; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008958:Models, Molecular; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D017368:Protein Prenylation; D040901:Proteomics; D012160:Retina / Q000002:abnormalities* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000002:abnormalities / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D020727:ADP-Ribosylation Factors; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D010744:Phosphoric Monoester Hydrolases; D029961:Zebrafish Proteins; D000099182:Phosphoinositide 5-Phosphatases; C517432:PDE6D protein, human; C490247:ARL3 protein, human