Extremely Rare Gene Variants May Drive Risk of Age-Related Macular Degeneration (AMD)

by Nai Ye Yeat
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A recent study from the National Eye Institute (NEI) identified extremely rare genetic variants that may point to one of the general mechanisms causing age-related macular degeneration (AMD), a common cause of vision loss in older adults.

The variants generate malformed proteins that alter the stability of the membrane attack complex (MAC), which will subsequently cause a chronic inflammatory response in the retina. The findings published in the journal iScience, suggested MAC as a potential therapeutic target to decelerate or prevent the progression of AMD.

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Age-related macular degeneration (AMD) is an acquired degeneration of the retina that causes significant central visual impairment. So far, there are many known genetic variants that increase the risk of developing AMD, while environmental, nutritional, and developmental processes will also interact in the process of degeneration observed in the macula lutea. 

However, the contribution of each of these genetic changes to AMD is small. Thus, scientists aimed to discover genetic variants and proteins that link directly to the disease.

Novel Therapeutic Target for AMD Identified

The investigative team had collected information for hundreds of patients and families with a high number of individuals with AMD. They searched for families carrying very rare AMD-causing variants and where the variant directly affects protein structure and function, as scientists believed those rare variants may reveal the root cause of the disease.  

In four identified families, the analysis showed individuals with AMD had mutations in complement component 8 (C8) proteins: C8-alpha and C8-beta. Variants from all 4 families affected the ability of the C8 protein to stick to each other, altering how MAC behaves in the retina. 

MAC forms a circular pore closed by C8 proteins and the pore permits the flow of ions through the outer membrane of cells, the final step in the complement cascade. The original function of MAC is to insert into bacterial cell membranes, while recent research has shown the complex role of MAC in regulating inflammatory processes in tissues, including in the retina. 

To conclude, as MAC is the final step of the immune system’s complement pathway, and there’s such a strong link between these rare variants and disease, researchers believed that it may be a more effective strategy to control AMD. The next focus of scientists would be developing small molecule drugs to control how strongly MAC drives inflammation, thus slowing down the progression of AMD.

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