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Understanding the molecular mechanisms underlying retina degeneration in INPP5E-Joubert Syndrome

Ali Sakawa Sharif, Christin Hanke-Gogokhia, Jeanne M Frederick, Wolfgang Baehr | Investigative Ophthalmology & Visual Science | July 2018 | Vol.59 | 3068


Purpose Mutations in INPP5E are associated with Joubert syndrome and MORM disease (mental retardation, truncal obesity, retinal dystrophy and micropenis). Joubert syndrome is a syndromic ciliopathy that includes ataxia, hyperpnea, abnormal eye and tongue movements, polydactyly and retinitis pigmentosa. To date, the function of INPP5E is unclear. Germline deletion of INPP5E is embryonically lethal in mouse, therefore, we sought to study INPP5E function by generating retina- and photoreceptor-specific knockouts. Our goal is to identify the onset of degeneration and devise gene-based therapies to ameliorate or cure the retina disease.

Methods Conditional Inpp5e knockout mice were generated by mating Inpp5eflox/flox mice with Six3-Cre, iCre75, or inducible ET-Cre transgenic mice. Mating of floxed mice with various Cre-expressing mice excises Inpp5e exons 2-6 in photoreceptor progenitors, rods or mature photoreceptors, respectively. Deletion of exons 2-6 removes much of the INPP5E phosphatase domain. Retina phenotypes are subsequently characterized by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT), rotarod performance test, OptoMotry, confocal immunohistochemistry using a battery of outer segment-related antibodies, transmission electron microscopy and immunoblotting.



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