Global collaboration cracks genetic code of debilitating eye disease

Cross-section of a retinal organoid exposed to deoxysphingolipids, showing cell death.

Cell death (green) is observed in cross-section of a retinal organoid exposed to deoxysphingolipids. Photoreceptors appear red in this image, cell nuclei appear blue. (Photo credit: Lowy Medical Research Institute / Kevin Eade)

An international research collaboration has identified two genes that cause MacTel 2, an untreatable eye disease which causes loss of central vision affecting two million people worldwide.

The research, published today in the New England Journal of Medicine, links low levels of the amino acid serine, to Mactel 2, leading to a build up of a toxic lipid in the retina which causes the death of photoreceptors cells which are essential for sight.

It also sheds light on the link between MacTel 2 and a rare peripheral neuropathy, known as HSAN1, which causes severe weakness and numbness in the hands and feet and is caused by variants in the same two genes.

The findings pave the way for potential future treatments for MacTel 2 and provides important clues for researchers studying other macular and other neurodegenerative diseases.

The research, led by Professor Martin Friedlander, president of the Lowy Medical Research Institute and professor at Scripps Medical Institute, has involved a unique mix of scientists and clinicians from the US, UK and Australia who have worked together for 15 years.

Centre for Eye Research Australia’s Professor Robyn Guymer has been part of the consortium since its foundation and several local patients with MacTel 2 and HSAN 1 participated in the study published today.

“This study has been the result of a unique, multifaceted international effort from scientists and clinicians, using astute clinical observation along with clues from genetics and metabolomics,” she said.

“One of the first clues came from the clinical teams, who noticed that there were people with both the rare eye disease MacTel and also the rare peripheral neuropathy. This then set the direction of research that lead to this discovery.”

Professor Guymer said the discovery raised hopes of developing treatments that could be taken to clinical trial.

“This international research effort would not be possible without the generosity of the Lowy Medical Research Institute. It brings hope of trialling treatments for a disease which up to now has been considered untreatable.”

The research was funded by the Lowy Medical Research Institute, Australian National Health and Medical Research Council, National Eye Institute (US), National Institutes of Health (US) and National Science Foundation (US).

Publication Information

JOURNAL: New England Journal of Medicine

DOI: 10.1056/NEJMoa1815111


Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy


Marin L. Gantner, Kevin Eade, Martina Wallace, Michal K. Handzlik, Regis Fallon, Jennifer Trombley, Roberto Bonelli, Sarah Giles, Sarah Harkins-Perry, Tjebo F.C. Heeren, Lydia Sauer, Yoichiro Ideguchi, Michelle Baldini, Lea Scheppke, Michael I. Dorrell, Maki Kitano, Barbara J. Hart, Carolyn Cai, Takayuki Nagasaki, Mehmet Badur, Mali Okada, Sasha Woods, Catherine Egan, Mark Gillies, Robyn Guymer, Florian Eichler, Melanie Bahlo, Marcus Fruttiger, Rando Allikmets, Paul S. Bernstein, Christian M. Metallo, Martin Friedlander.

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