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

Authors :
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
Harvard Medical School [Boston] (HMS)
Source :
Human Mutation, Human Mutation, Wiley, 2014, 35 (1), pp.137-146. ⟨10.1002/humu.22470⟩
Publication Year :
2014
Publisher :
HAL CCSD, 2014.

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.

Subjects

Subjects :
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

Details

Language :
English
ISSN :
10597794 and 10981004
Database :
OpenAIRE
Journal :
Human Mutation, Human Mutation, Wiley, 2014, 35 (1), pp.137-146. ⟨10.1002/humu.22470⟩
Accession number :
edsair.doi.dedup.....7ea54b2a50db5d77c8971d0cf7982565