title: Patient-specific induced pluripotent stem cells to evaluate the pathophysiology of TRNT1-associated Retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) is a heterogeneous group of monogenic disorders characterized by progressive death of the light-sensing photoreceptor cells of the outer neural retina. We recently identified novel hypomorphic mutations in the tRNA Nucleotidyl Transferase, CCA-Adding 1 (TRNT1) gene that cause early-onset RP. To model this disease in vitro, we generated patient-specific iPSCs and iPSC-derived retinal organoids from dermal fibroblasts of patients with molecularly confirmed TRNT1-associated RP. Pluripotency was confirmed using rt-PCR, immunocytochemistry, and a TaqMan Scorecard Assay. Mutations in TRNT1 caused reduced levels of full-length TRNT1 protein and expression of a truncated smaller protein in both patient-specific iPSCs and iPSC-derived retinal organoids. Patient-specific iPSCs and iPSC-derived retinal organoids exhibited a deficit in autophagy, as evidenced by aberrant accumulation of LC3-II and elevated levels of oxidative stress. Autologous stem cell-based disease modeling will provide a platform for testing multiple avenues of treatment in patients suffering from TRNT1-associated RP.
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: tasneem-sharma@uiowa.edu.
authors.forename: Tasneem P
authors.initials: TP
authors.lastname: Sharma
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: luke-wiley@uiowa.edu.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Wiley
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: steven-whitmore@uiowa.edu.
authors.forename: S Scott
authors.initials: SS
authors.lastname: Whitmore
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: kristin-anfinson@uiowa.edu.
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Anfinson
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: cathryn-cranston@uiowa.edu.
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Cranston
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: douglas-oppedal@uiowa.edu.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Oppedal
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: heather-daggett@uiowa.edu.
authors.forename: Heather T
authors.initials: HT
authors.lastname: Daggett
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: robert-mullins@uiowa.edu.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: budd-tucker@uiowa.edu.
authors.forename: Budd A
authors.initials: BA
authors.lastname: Tucker
authors.affiliation: Stephen A Wynn Institute for Vision Research, Department of Ophthalmology and Visual Science, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: edwin-stone@uiowa.edu.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
mesh_terms: D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009713:Nucleotidyltransferases / Q000378:metabolism*; D009940:Organoids / Q000378:metabolism; D018384:Oxidative Stress; D012160:Retina / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000473:pathology* / Q000503:physiopathology*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D009713:Nucleotidyltransferases; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C477012:MAP1LC3A protein, human; C000610948:TRNT1 protein, human
keywords: Autophagy; Induced pluripotent stem cells; Oxidative stress; Retinal organoids; Retinitis pigmentosa; TRNT 1