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HomeminewsScientists Identify Genetic Markers for Rare Eye Diseases

Scientists Identify Genetic Markers for Rare Eye Diseases

Researchers from the National Institutes of Health (NIH) have made a breakthrough in understanding the genetic underpinnings of a group of neurodegenerative disorders that can severely impact vision and mobility. Their findings, published in the journal Brain, reveal how mutations in the PNPLA6 gene disrupt an important enzyme called neuropathy target esterase (NTE), leading to conditions like Boucher-Neuhäuser syndrome and Oliver-McFarlane syndrome. 

The PNPLA6 gene codes for the NTE enzyme, which plays a crucial role in regulating lipid metabolism and maintaining neuronal membrane stability. When mutations occur in this gene, NTE function is impaired, resulting in a cascade of effects that can damage nerves controlling vision, movement, and hormone regulation. 

By analysing data from over 100 patients with PNPLA6 mutations, the NIH team pinpointed how different genetic variants impact disease severity. They found that single nucleotide substitutions, known as missense mutations, are the driving force behind these disorders. Missense mutations swap one nucleotide base for another in the gene sequence, altering the amino acids that make up the NTE protein. 

Using neuroimaging, electrophysiology studies, and genetic analysis to map the clinical effects based on the mutation location, Dr Robert Hufnagel, lead researcher from the National Eye Institute’s Ophthalmic and Visual Function Branch and his team, discovered that how the mutations affected NTE function depended on where they occur in the PNPLA6 gene sequence.  

When mutations occur in this gene, NTE function is impaired, resulting in a cascade of effects that can damage nerves controlling vision, movement, and hormone regulation

Mouse Models 

To validate their human findings, the researchers engineered mouse models carrying the same PNPLA6 missense mutations seen in patients. Remarkably, mice with higher residual NTE activity exhibited milder disease symptoms, establishing a clear link between enzyme function and clinical severity. 

“In our mouse experiments, we observed that greater NTE activity associated with less profound disease,” said Dr James Liu, a postdoctoral fellow and study author. “This knowledge will enable us to learn more about the spectrum of PNPLA6-related diseases in humans and positions us for future clinical trials, potentially using NTE as a biomarker.” 

The identification of NTE as a biomarker holds significant promise for earlier diagnosis and targeted therapy development for PNPLA6-linked disorders. By quantifying NTE levels, clinicians may be able to predict disease progression and severity, streamlining the path to more personalized treatment approaches. 

Dr Hufnagel’s team is now focussed on further elucidating the molecular mechanisms by which PNPLA6 mutations compromise neuronal health and function. With a deeper understanding of this pathology, new therapeutic avenues could open up for preserving vision and preventing blindness in individuals affected by these devastating genetic conditions.  


Liu J., He Y., Synofzik M., Hufnagel R.B., et al., Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders. Brain. 2024;awae055. https://DOI.org/10.1093/brain/awae055