June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
The serine biosynthetic enzyme, PHGDH, is essential for retinal health
Author Affiliations & Notes
  • Marin Gantner
    Lowy Medical Research Institute, California, United States
  • Regis Fallon
    Lowy Medical Research Institute, California, United States
  • Yoichiro Ideguchi
    The Scripps Research Institute, La Jolla, California, United States
  • Caleb Bates
    Lowy Medical Research Institute, California, United States
  • Michal Handzlik
    Salk Institute for Biological Studies, La Jolla, California, United States
  • Martina Wallace
    Dublin City University, Dublin, Ireland
  • Christian Metallo
    Salk Institute for Biological Studies, La Jolla, California, United States
  • Martin Friedlander
    The Scripps Research Institute, La Jolla, California, United States
    Lowy Medical Research Institute, California, United States
  • Footnotes
    Commercial Relationships   Marin Gantner None; Regis Fallon None; Yoichiro Ideguchi None; Caleb Bates None; Michal Handzlik None; Martina Wallace None; Christian Metallo None; Martin Friedlander None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 870. doi:
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      Marin Gantner, Regis Fallon, Yoichiro Ideguchi, Caleb Bates, Michal Handzlik, Martina Wallace, Christian Metallo, Martin Friedlander; The serine biosynthetic enzyme, PHGDH, is essential for retinal health. Invest. Ophthalmol. Vis. Sci. 2022;63(7):870.

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

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Abstract

Purpose : Macular telangiectasia type II (MacTel) is a late onset macular disease leading to progressive vision loss. Previous work determined that low circulating levels of serine in MacTel patients is associated with retinal dysfunction. Whole exome sequencing studies found that rare variants in PHGDH, the rate limiting enzyme in serine synthesis, account for a significant fraction of the disease. The purpose of this study was to determine the potential impact of reduced PHGDH function on retinal health.

Methods : To test the rate of serine and glycine biosynthesis in the retina, as well as uptake of these amino acids from the circulation, we used heavy carbon (C13) labeled glucose, serine or glycine coupled with mass spectrometry. To determine the consequences of reduced PHGDH activity on retinal health we used mice heterozygous for PHGDH and monitored their retinal function and metabolite levels.

Results : We determined that the neural retina and RPE/choroid exhibit high de novo serine synthesis, comparable to that in the brain. Additionally, a large portion of retinal serine originates in the circulation. Mice with reduced PHGDH function have altered circulating, retinal and RPE metabolite levels. Electroretinogram (ERG) measurements in mice indicate visual impairment with reduced PHGDH activity.

Conclusions : The high rate of serine biosynthesis, as well as uptake from the circulation, suggests that the serine pool in the retina is highly dynamic. Variants in PHGDH that impair enzyme function, as observed in a subset MacTel patients, are sufficient to generate metabolite defects and drive retinal dysfunction.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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