July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Investigating the Effect of a PEX6 Mutation on Peroxisome Structure and Function
Author Affiliations & Notes
  • Matthew David Benson
    Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada
  • Ian M MacDonald
    Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada
  • Footnotes
    Commercial Relationships   Matthew Benson, None; Ian MacDonald, None
  • Footnotes
    Support  Foundation Fighting Blindness Grant - Clinician-Scientist Emerging Leader Award
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 406. doi:
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      Matthew David Benson, Ian M MacDonald; Investigating the Effect of a PEX6 Mutation on Peroxisome Structure and Function. Invest. Ophthalmol. Vis. Sci. 2019;60(9):406.

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

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Purpose :
Peroxisomal biogenesis disorders (PBDs) represent a group of conditions that cause severe vision loss, sensorineural hearing loss, neurologic dysfunction, and other systemic abnormalities due to abnormal peroxisomal function. An appropriate therapy is needed as there are no disease-modifying treatments currently available for this condition. Our lab identified a PBD in a 12-year old child with compound heterozygous PEX6 mutations resulting in severe congenital sensorineural hearing loss and retinopathy. Our study seeks to examine the effect of mutations in PEX6 on peroxisome structure and function and investigate a potential therapeutic intervention for these patients.

Methods : Our patient underwent serum biochemical analysis and genetic panel testing to confirm the diagnosis of a peroxisomal biogenesis disorder. He had an ophthalmic assessment including Goldmann visual fields and optical coherence tomography of his maculae. To investigate the effect of changes in PEX6 on the peroxisomes, an in vitro PEX6 knockdown assay was performed in cultured HeLa cells. Western blot analysis with antibodies against an endogenous peroxisomal membrane protein, PMP70, was performed to investigate the effect of PEX6 knockdown on peroxisome number.

Results :
Gene panel testing in our patient revealed compound heterozygous variants (c.802_815del; c.35T>C) in PEX6. Biochemical analysis of his serum revealed elevated very long chain fatty acids; a brain MRI revealed diffuse white matter changes in keeping with a peroxisomal disorder. An in vitro siRNA assay achieved approximately 80% PEX6 knockdown efficiency. There was no difference in PMP70 levels in PEX6 siRNA treated cells compared with control siRNA cells.

Conclusions : Compound heterozygous mutations in PEX6 are responsible for combined sensorineural hearing loss and retinopathy in our patient, a phenotype that can mimic Usher syndrome. Preliminary PEX6 knockdown studies did not demonstrate a reduction in PMP70, as initially hypothesized. We hypothesize that 80% knockdown is insufficient to recapitulate an autosomal recessive condition in our patient or that PMP70 is present in PEX6 knockdown cells but the resulting peroxisome morphology is abnormal. Future studies will analyze peroxisome number and morphology using immunofluorescence and microscopy in PEX6 knockdown cells and in skin-derived patient fibroblasts.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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