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Functional Characterization and Rescue of a Deep Intronic Mutation in OCRL Gene Responsible for Lowe Syndrome
Author(s) -
Rendu John,
Montjean Rodrick,
Coutton Charles,
Suri Mohnish,
Chicanne Gaetan,
Petiot Anne,
Brocard Julie,
Grunwald Didier,
Pietri Rouxel France,
Payrastre Bernard,
Lunardi Joel,
Dorseuil Olivier,
Marty Isabelle,
Fauré Julien
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23139
Subject(s) - biology , exon , mutation , genetics , tubulopathy , medicine , endocrinology , gene , kidney
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.