Mechanisms of myopia: the key role of the DUSP4 gene

Myopia, a poorly understood global epidemic

According to the WHO, the number of myopic people in the world could exceed 5 billion by 2050. However, high myopia can lead to serious complications such as retinal detachment or macular degeneration, eventually leading to blindness. Understanding the origin of myopia is therefore a major challenge in public health. While it has been established that the onset of myopia depends on both environmental factors such as light and genetic predispositions, these mechanisms remain to be elucidated.

The discovery of the team led by Isabelle Audo and Christina Zeitz at the Institut de la Vision provides an answer to this gene-environment interaction in the development of myopia. By showing the direct link between DUSP4 gene expression, eye growth mechanisms and retinal signaling in response to light, they open the door to new avenues to understand the mechanisms underlying vision disorders, in order to better prevent and treat them.

A discovery resulting from basic research on rare diseases

Before reaching the DUSP4 gene, the genetics team at the Institut de la Vision was working on the genetic causes of congenital stationary night blindness. This rare disease is associated with impaired vision in the dark, but also with high myopia. Christina Zeitz and her colleagues have hypothesized that the inactivation of certain genes involved in congenital stationary night blindness could trigger a cascade of alterations which, by affecting certain mechanisms of retinal growth, would contribute to the development of myopia.

In a previous publication**, the team and its collaborators at the Institut de la Vision had identified 52 genes whose expression was impacted by the different forms of congenital stationary night blindness. By analyzing the scientific literature, they showed that half of them were associated with myopia. Among them, the DUSP4  gene caught the attention of the authors of the new study. Indeed, while its functionality was still unknown in the retina, it was well expressed in the inner layers of the retina that are probably important for the development and protection of myopia.

Christina Zeitz and researcher Baptiste Wilmet have therefore studied the role of DUSP4 in detail. In particular, they showed that this gene is expressed in the bipolar cells of the retina, which transmit light signals to the neurons responsible for vision. The absence of DUSP4 induces an imbalance in these cells that impacts two essential neural pathways, known as "ON" and "OFF", which process incoming light signals. This imbalance alters the release of dopamine, a neuromediator essential for the healthy development of the eye, making it more vulnerable to environmental factors that promote myopia.

A missing link in the understanding of myopia 

These results reveal a novel mechanism directly linking light signaling and retinal neural pathways to ocular growth. The discovery of the role of DUSP4 sheds new light: far from being just another gene associated with myopia, it stands out for its importance in the light-dependent regulation of dopamine and ON/OFF pathways, making it a unique point of convergence between genetic and environmental factors of myopia.

The clarification of its mechanism could explain why some individuals are more sensitive to myopia, and provide potential therapeutic targets. Researchers at the congenital stationary night blindnes Institut de la Vision are continuing their work to understand how DUSP4 interacts with other genes involved in myopia, as well as its role in other retinal diseases.