June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Residual Neuropathy Target Esterase activity predicts retinopathy among PNPLA6 disorders
Author Affiliations & Notes
  • James Liu
    Medical Genetics and Ophthalmic Genomics Unit,, National Eye Institute, Bethesda, Maryland, United States
  • Yi He
    Fermentation Facility, Biochemistry and Biophysics Center, National Heart Lung and Blood Institute, Bethesda, Maryland, United States
  • Chisom Madu
    School of Medicine, City University of New York, New York, New York, United States
    Medical Genetics and Ophthalmic Genomics Unit,, National Eye Institute, Bethesda, Maryland, United States
  • Lijin Dong
    Genetic Engineering Core Facility, National Eye Institute, Bethesda, Maryland, United States
  • Marina Han
    Neuroscience Graduate Program, University of Washington, Seattle, Washington, United States
    Medical Genetics and Ophthalmic Genomics Unit,, National Eye Institute, Bethesda, Maryland, United States
  • Cara Lwin
    Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
    Medical Genetics and Ophthalmic Genomics Unit,, National Eye Institute, Bethesda, Maryland, United States
  • Gavin Arno
    Institute of Ophthalmology, University College London, London, London, United Kingdom
    Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Anthony Moore
    Institute of Ophthalmology, University College London, London, London, United Kingdom
    Ophthalmology, University of California San Francisco, San Francisco, California, United States
  • Andrew R Webster
    Institute of Ophthalmology, University College London, London, London, United Kingdom
    Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Michel Michaelides
    Institute of Ophthalmology, University College London, London, London, United Kingdom
    Moorfields Eye Hospital NHS Foundation Trust, London, London, United Kingdom
  • Laryssa Huryn
    Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, United States
  • Bin Guan
    Medical Genetics and Ophthalmic Genomics Unit,, National Eye Institute, Bethesda, Maryland, United States
  • Robert B. Hufnagel
    Medical Genetics and Ophthalmic Genomics Unit,, National Eye Institute, Bethesda, Maryland, United States
  • Footnotes
    Commercial Relationships   James Liu None; Yi He None; Chisom Madu None; Lijin Dong None; Marina Han None; Cara Lwin None; Gavin Arno None; Anthony Moore None; Andrew Webster None; Michel Michaelides None; Laryssa Huryn None; Bin Guan None; Robert Hufnagel None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 578. doi:
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    • Get Citation

      James Liu, Yi He, Chisom Madu, Lijin Dong, Marina Han, Cara Lwin, Gavin Arno, Anthony Moore, Andrew R Webster, Michel Michaelides, Laryssa Huryn, Bin Guan, Robert B. Hufnagel; Residual Neuropathy Target Esterase activity predicts retinopathy among PNPLA6 disorders. Invest. Ophthalmol. Vis. Sci. 2023;64(8):578.

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

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Abstract

Purpose : Pathogenic variants in the PNPLA6 gene cause a broad spectrum of neurological disorders such as spastic paraplegia type 39 (SPG39), Gordon-Holmes syndrome (GHS), Boucher-Neuhauser syndrome (BNHS), Laurence-Moon syndrome (LMS), and Oliver-McFarlane syndrome (OMS). PNPLA6 encodes Neuropathy Target Esterase (NTE), yet it remains unclear why NTE enzymatic dysfunction causes retinopathy in a subset of patients. Here, we investigate the relationship between PNPLA6 enzymatic activity and retinal degeneration in human and mouse.

Methods : Clinical meta-analysis was performed on previously reported (PubMed, 2008-2022) and newly recruited patients. DNA constructs encoding full length NTE underwent site directed mutagenesis to produce the patient specific proteins. NTE activity was determined as previously published (PMID:12791540). Mouse visual function and structure assays were performed on Espion E2 system, Optodrum, and Spectralis. Statistical analysis was performed in Prism.

Results : Biallelic pathogenic PNPLA6 variants were detected in 20 patients with clinical diagnosis of SPG39, BNHS or OMS, including 17 novel variants. Clinical meta-analysis of 115 individuals indicated significant differences in ophthalmic and endocrinologic symptom onset between clinical diagnosis categories. Intriguingly, missense variants located within the enzymatic domain associated more frequently with more severe forms of the disease (BNHS,OMS). To examine effects of missense alleles on disease onset, we measured esterase activity in 74 variants observed across PNPLA6-associated clinical diagnoses. Residual esterase activity was significantly lower in patients with retinopathy and endocrinopathy. A mouse allelic series demonstrated that residual activity correlated with both viability and retinopathy. Mice with residual activity similar to OMS patients exhibit reduced retinal function, visual acuity, and retinal thickness compared to littermate controls.

Conclusions : The severity of PNPLA6 disorders and presence of retinal disease is driven by residual NTE activity. Enzyme activity of disease-associated missense variants indicates a relationship between enzymatic activity and likelihood of retinopathy and endocrinopathy, implicating missense variants as drivers of tissue-specific disease onset. This supports a novel genotype:activity:phenotype relationship among PNPLA6-opathies that may be valuable for both diagnosis and prognosis.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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