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PEX6 Mutations in Peroxisomal Biogenesis Disorders: An Usher Syndrome Mimic
Matthew D Benson1, Kimberly M Papp1, Geoffrey A Casey2
1Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada.
Ophthalmology Science
|October 17, 2022
Summary
Peroxisomal biogenesis disorders (PBDs) caused by PEX6 gene mutations impair protein import. Overexpressing PEX6 in cells shows promise for restoring peroxisome function and potential therapeutic benefit.
Area of Science:
- Cell biology
- Genetics
- Medical genetics
Background:
- Peroxisomal biogenesis disorders (PBDs) are a group of genetic conditions.
- PBDs result from mutations in PEX genes, leading to impaired peroxisomal function.
- Current treatments for PBDs are lacking.
Purpose of the Study:
- Investigate the disease mechanism of PBDs caused by PEX6 gene defects.
- Determine if PEX6 overexpression can restore peroxisome function.
- Explore potential therapeutic benefits of PEX6 restoration.
Main Methods:
- Studied patient-derived skin fibroblasts with PEX6 mutations.
- Developed a PEX6 knockout cell line using CRISPR-Cas9 technology.
- Assessed peroxisome number and matrix protein import via immunoblot and immunofluorescence.
Main Results:
- Patient fibroblasts showed impaired peroxisomal matrix protein import, not reduced peroxisome number.
- PEX6 knockout cells exhibited fewer peroxisomes and impaired protein import.
- Overexpression of PEX6 improved matrix protein import in PEX6 knockout cells.
Conclusions:
- PEX6 mutations cause PBDs primarily through impaired protein import.
- Restoring PEX6 function offers a potential therapeutic strategy for PBDs.
- Further research using patient-specific stem cells may elucidate retinal PEX6 roles and gene therapy potential.
Keywords:
CRISPR, clustered regularly interspaced short palindromic repeatsDTM, docking translocation moduleGFP, green fluorescent proteinHEK293T, human embryonic kidney 293THearing lossPBD, peroxisomal biogenesis disorderPBS, phosphate-buffered salinePEX6PTS1, peroxisomal targeting signal 1PTS2, peroxisomal targeting signal 2Peroxisomal biogenesis disordersPeroxisomeRPE, retinal pigment epitheliumRetinal degenerationUsher syndromeWT, wild-type
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