title: Functional Characterization and Rescue of a Deep Intronic Mutation in OCRL Gene Responsible for Lowe Syndrome.
abstract: Dent-2 disease and Lowe syndrome are two pathologies caused by mutations in inositol polyphosphate 5-phosphatase OCRL gene. Both conditions share proximal tubulopathy evolving to chronic kidney failure. Lowe syndrome is in addition defined by a bilateral congenital cataract, intellectual disability, and hypotonia. The pathology evolves in two decades to a severe condition with renal complications and a fatal issue. We describe here a proof of principle for a targeted gene therapy on a mutation of the OCRL gene that is associated with Lowe syndrome. The affected patient bears a deep intronic mutation inducing a pseudo-exon inclusion in the mRNA, leading to a OCRL-1 protein loss. An exon-skipping strategy was designed to correct the effect of the mutation in cultured cells. We show that a recombinant U7-modified small RNA efficiently triggered the restoration of normal OCRL expression at mRNA and protein levels in patient's fibroblasts. Moreover, the PI(4,5)P2 accumulation and cellular alterations that are hallmark of OCRL-1 dysfunction were also rescued. Altogether, we provide evidence that the restoration of OCRL-1 protein, even at a reduced level, through RNA-based therapy represents a potential therapeutic approach for patients with OCRL splice mutations.
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.|Biochimie Génétique et Moléculaire, CHU Grenoble Alpes, France.
authors: John
authors: J
authors: Rendu
authors: Institut Cochin, INSERM U1016, Paris, France.|CNRS UMR8104, Université Paris Descartes, Paris, France.
authors: Rodrick
authors: R
authors: Montjean
authors: Laboratoire de Génétique Chromosomique, CHU Grenoble Alpes, France.
authors: Charles
authors: C
authors: Coutton
authors: Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
authors: Mohnish
authors: M
authors: Suri
authors: I2MC, INSERM U1048, Toulouse, France.|Laboratoire d'Hématologie, CHU de Toulouse, France.
authors: Gaetan
authors: G
authors: Chicanne
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.
authors: Anne
authors: A
authors: Petiot
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.
authors: Julie
authors: J
authors: Brocard
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.
authors: Didier
authors: D
authors: Grunwald
authors: Research Center of Myology, INSERM UMRS974, Paris, France.|CNRS FRE3617, UPMC, Paris, France.
authors: France
authors: F
authors: Pietri Rouxel
authors: I2MC, INSERM U1048, Toulouse, France.|Laboratoire d'Hématologie, CHU de Toulouse, France.
authors: Bernard
authors: B
authors: Payrastre
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.|Biochimie Génétique et Moléculaire, CHU Grenoble Alpes, France.
authors: Joel
authors: J
authors: Lunardi
authors: Institut Cochin, INSERM U1016, Paris, France.|CNRS UMR8104, Université Paris Descartes, Paris, France.
authors: Olivier
authors: O
authors: Dorseuil
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.
authors: Isabelle
authors: I
authors: Marty
authors: Cellular Myology and Pathology, INSERM, U1216, Grenoble, France.|Grenoble Institut of Neurosciences, Université Grenoble Alpes, France.|Biochimie Génétique et Moléculaire, CHU Grenoble Alpes, France.
authors: Julien
authors: J
authors: Fauré
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D002675:Child, Preschool; D004789:Enzyme Activation; D005091:Exons; D005347:Fibroblasts; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D057054:Molecular Imaging; D009154:Mutation; D009800:Oculocerebrorenal Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human
keywords: Lowe syndrome; OCRL; U7; exon skipping