Genetic Insights to Rare Eye Disease MacTel

Article: Genetic discovery gives insight into causes of eye disease
Source: Walter and Eliza Hall Institute (Australia), via ScienceDaily
Published: March 17, 2021
Article: New genetic links found to rare eye disease
Source: Scripps Research Institute, via NEI
Published March 22, 2021
Article: Researchers Uncover Potential Cause of Rare Eye Disease
Source: Genetic Engineering & Biotechnology News
Published: March 24, 2021

Electron microscopy of human retinal cells in MacTel

Macular telangiectasia type 2 (MacTel) is a rare eye disease that affects levels of amino acids in the eye, with both metabolic and genetic risk factors. MacTel affects roughly one in 5,000 people or two million people worldwide. An international study identified 22 gene variants that contribute to this degenerative macular disease. In particular, the research team found that variants of one gene encoding the rate-limiting serine biosynthetic enzyme phosphoglycerate dehydrogenase (PHGDH) were significantly associated with MacTel patients; the 22 variants of PHGDH together contribute to 3-4% of MacTel cases. While previous studies drew connections between MacTel and low levels of the amino acid serine, the discovery of the PHGDH gene was the long-sought missing link. Serine in turn is essential for the metabolic health and function of neurons in the eye and elsewhere in the body. Only one allele of the PHGDH gene needs to be affected to result in partial loss of enzyme function, leading to macular deterioration. Using human induced pluripotent stem cells, the researchers then confirmed that a PHGDH mutation leads to the production of toxic deoxysphingolipids (deoxySLs) previously shown to cause MacTel. Also of basic scientific interest is the genetic analysis of "groups of mutations" instead of individual mutations as in previous studies; the new analysis method was useful for identifying genes in small population sizes of people affected by rare diseases. These genetic studies provide valuable information toward better understanding and treatment of this rare eye disease.

Personal commentary: Sources vary in reporting the number of gene variants discovered, from seven to twenty two, perhaps partly due to the fact that this is a collaborative project with contributions from several research centers and published in multiple journals.

My rating of this study: ⭐⭐⭐🌸

Further reading: Hyper-Reflectivity in MacTel Linked With Near Complete Retinal Sensitivity Loss

Bonelli, R., Jackson, V.E., Prasad, A., et al. "Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder." Communications Biology. 4(274). 2 March 2021. http://doi.org/10.1038/s42003-021-01788-w

Eade, K., Gantner, M.L., Hostyk, J.A., et al. "Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease." Nature Metabolism. 3:366–377. 22 March 2021. http://doi.org/10.1038/s42255-021-00361-3