June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
TRNT1 MUTATIONS LINKED TO EARLY ONSET AUTOSOMAL RECESSIVE RETINITIS PIGMENTOSA
Author Affiliations & Notes
  • Tasneem Putliwala Sharma
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Robert F Mullins
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Todd E Scheetz
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Jessica Penticoff
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Malia Collins
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Trudi Westfall
    Biology, University of Iowa, Iowa City, IA
  • Jenna Barnes
    Biology, University of Iowa, Iowa City, IA
  • Diane C Slusarski
    Biology, University of Iowa, Iowa City, IA
  • Budd Tucker
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Edwin M Stone
    Ophthalmology & Visual Sciences, Stephen A. Wynn Institute for Vision Research, Carver College of Medicine, University of Iowa, Iowa City, IA
  • Footnotes
    Commercial Relationships Tasneem Sharma, None; Robert Mullins, None; Todd Scheetz, None; Jessica Penticoff, None; Malia Collins, None; Trudi Westfall, None; Jenna Barnes, None; Diane Slusarski, None; Budd Tucker, None; Edwin Stone, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2893. doi:
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      Tasneem Putliwala Sharma, Robert F Mullins, Todd E Scheetz, Jessica Penticoff, Malia Collins, Trudi Westfall, Jenna Barnes, Diane C Slusarski, Budd Tucker, Edwin M Stone; TRNT1 MUTATIONS LINKED TO EARLY ONSET AUTOSOMAL RECESSIVE RETINITIS PIGMENTOSA. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2893.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Retinitis pigmentosa (RP), a heterogeneous group of monogenic disorders, is characterized by a variety of symptoms including night blindness and progressive death of photoreceptors. Through whole-exome sequencing, we recently identified novel mutations in the tRNA Nucleotidyl Transferase, CCA-Adding, 1 (TRNT1) gene in a proband displaying early-onset RP. Mutations in TRNT1 have been previously implicated in congenital sideroblastic anemia. The purpose of this study was 1) to demonstrate that TRNT1 mutations are causative of nonsyndromic autosomal recessive RP and 2) to elucidate the pathophysiologic mechanism of newly identified TRNT1 mutations in photoreceptor cell dysfunction and death.

Methods: Next generation whole exome sequencing was used to identify potential disease-causing mutations in a proband with clinically diagnosed early onset autosomal recessive RP. Zebrafish, human induced pluripotent stem cells (iPSC), gene addition transfer, and CRISPR/Cas9-mediated genome editing technologies were used to confirm pathogenicity and develop potential treatment strategies.

Results: Whole exome sequencing revealed two potential disease-causing mutations in the gene TRNT1. Morpholino-mediated knockdown of TRNT1 in zebrafish caused a visual function defect that could in part be rescued by injection of wild-type RNA. Dermal fibroblasts from the proband were expanded and targeted for iPSC generation. IPSC pluripotency was confirmed using standard rt-PCR, immunoblotting, immunocytochemistry and teratoma formation. The genetic mutations identified via whole exome sequencing were confirmed to alter retinal TRNT1 transcript and cause loss of full-length TRNT1 protein in iPSC-derived retinal progenitor cells.

Conclusions: Mutations in TRNT1 are capable of causing early onset, non-syndromic autosomal recessive RP. We have generated patient-specific iPSC-derived retinal cells to model disease in vitro. These cells will allow us to learn more about the pathophysiology and test multiple avenues of treatment for TRNT1-associated RP.

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