title: OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells.
abstract: OCRL mutations are associated with both Lowe syndrome and Dent-2 disease, two rare X-linked conditions. Lowe syndrome is an oculo-cerebro-renal disorder, whereas Dent-2 patients mainly present renal proximal tubulopathy. Loss of OCRL-1, a phosphoinositide-5-phosphatase, leads in Lowe patients' fibroblasts to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) accumulation, with defects in F-actin network, α-actinin distribution and ciliogenesis, whereas fibroblasts of Dent-2 patients are still uncharacterized. To search for mechanisms linked to clinical variability observed between these two OCRL mutation-associated pathologies, we compared dermal fibroblasts from independent patients, four affected by Dent-2 disease and six with Lowe syndrome. For the first time, we describe that Dent-2 fibroblasts with OCRL loss-of-function (LOF) mutations exhibit decrease in actin stress fibers, appearance of punctate α-actinin signals and alteration in primary cilia formation. Interestingly, we quantified these phenotypes as clearly intermediate between Lowe and control fibroblasts, thus suggesting that levels of these defects correlate with clinical variations observed between patients with OCRL mutations. In addition, we show that Lowe and Dent-2 fibroblasts display similar PI(4,5)P2 accumulation levels. Finally, we analyzed INPP5B, a paralogous gene already reported to exhibit functional redundancy with OCRL, and report neither differences in its expression at RNA or protein levels, nor specific allelic variations between fibroblasts of patients. Altogether, we describe here differential phenotypes between fibroblasts from Lowe and Dent-2 patients, both associated with OCRL LOF mutations, we exclude direct roles of PI(4,5)P2 and INPP5B in this phenotypic variability and we underline potential key alterations leading to ocular and neurological clinical features in Lowe syndrome.
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Rodrick
authors.initials: R
authors.lastname: Montjean
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Rifdat
authors.initials: R
authors.lastname: Aoidi
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Pierrette
authors.initials: P
authors.lastname: Desbois
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Rucci
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Trichet
authors.affiliation: Service de Néphrologie Pédiatrique, Hôpital Necker Enfants Malades, Paris, France and.
authors.forename: Rémi
authors.initials: R
authors.lastname: Salomon
authors.affiliation: Laboratoire de Biochimie et Génétique Moléculaire, CHU de Grenoble, Grenoble, France.
authors.forename: John
authors.initials: J
authors.lastname: Rendu
authors.affiliation: Laboratoire de Biochimie et Génétique Moléculaire, CHU de Grenoble, Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Fauré
authors.affiliation: Laboratoire de Biochimie et Génétique Moléculaire, CHU de Grenoble, Grenoble, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Lunardi
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Gacon
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Paris, France, olivier.dorseuil@inserm.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dorseuil
mesh_terms: D000199:Actins / Q000378:metabolism; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D053040:Nephrolithiasis / Q000235:genetics* / Q000378:metabolism; D009800:Oculocerebrorenal Syndrome / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D000199:Actins; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C075695:OCRL protein, human