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Clinical science
Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report
  1. Laura Bryant1,
  2. Olga Lozynska1,
  3. Anson Marsh1,
  4. Tyler E Papp1,
  5. Lucas van Gorder1,
  6. Leona W Serrano2,
  7. Xiaowu Gai3,4,
  8. Albert M Maguire2,
  9. Tomas S Aleman2,
  10. Jean Bennett1
  1. 1Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  2. 2Department of Ophthalmology and CAROT, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania, USA
  3. 3Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California, USA
  4. 4Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  1. Correspondence to Dr Jean Bennett, Center for Advanced Retinal and Ocular Therapeutics (CAROT), Philadelphia, PA 19104, USA; jebennet{at}pennmedicine.upenn.edu; Dr Tomas S Aleman, Center for Advanced Retinal and Ocular Therapeutics (CAROT), Philadelphia, PA 19104, USA; aleman{at}pennmedicine.upenn.edu

Abstract

Background Variants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.

Methods We performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.

Results PRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.

Conclusions c.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

  • PRPF31gene
  • retinitis pigmentosa
  • genetic diagnosis
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bjophthalmol-2017-311405

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    Footnotes

    • Contributors TSA, LS and AMM carried out patient assessments and referred potential patients to the study. LB, OL, LvG, AM, TEP, XG and JB contributed to data collection and analyses. LB, TSA and JB wrote the manuscript. All authors reviewed the manuscript.

    • Funding This study was funded by NIH Vision Training Grant 5T32EY007035-37, a Center grant (#C-CL-0607-0389-UPA01) from Foundation Fighting Blindness to the CHOP-Penn Pediatric Center for Retinal Degenerations, the Brenda and Matthew Shapiro Stewardship and the Robert and Susan Heidenberg Investigative Research Fund for Ocular Gene Therapy, Research to Prevent Blindness, the Paul and Evanina Mackall Foundation Trust, the Center for Advanced Retinal and Ocular Therapeutics, and the F.M. Kirby Foundation.

    • Disclaimer The senior author (JB) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

    • Competing interests JB is a founder of Gensight Biologics and of Limelight Bio and a scientific (non-equity-holding) founder of Spark Therapeutics. JB holds Sponsored Research Agreements (SRAs) from Biogen, Limelight Bio and REGENXBio. The coauthors report no additional conflicts.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All materials generated in this study and all data will be available to other authors. Patient-derived samples will be available under a Material Transfer Agreement.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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