Genetic Mutation Responsible for Form of Macular Degeneration

Researchers are getting closer to understanding the pathogenesis of one type of age-related macular degeneration (AMD). In a paper published ahead of print in the journal Human Molecular Genetics, Ewan P. Ramsay of the Wellcome Trust Center for Cell-Matrix Research and the University of Manchester, and colleagues, described their work in investigating the mechanisms that lead to X-linked retinoschisis (XLRS), which they characterized as being “a monogenic form of macular degeneration.”

The researchers said, “In this study we analyze the assembly of retinoschisin through solution of the structure of the retinoschisin monomer coupled with cryo-EM analysis”. Retinoschisin is “an octameric retinal-specific protein,” they said, and “is essential for retinal architecture with mutations causing X-linked retinoschisis”.

“Despite the central role retinoschisin plays in the maintenance of retinal architecture, the mechanism by which it maintains the integrity of photoreceptor-bipolar cell synapses remains elusive,” the researchers noted, further describing the need for the present study.

Their analyses showed “a highly elongated structure” that “generates a ‘wedge’ shape which would allow for efficient assembly of the retinoschisin subunits into a ring structure.” They added, “The observation of mutation sites within the inter-octamer interface lead to the hypothesis that the hexadecamer complex may be required for retinoschisin function in the retina.”

Additionally, the researchers wrote, “The formation of a retinoschisin dimer of octamers complex would allow for co-localization of synaptic machinery on opposing membranes whilst providing structural support to the synapse.” If that complex were destabilized or lost, the researchers added there would be “loss of structural integrity and pathology.”

The authors concluded by suggesting that future studies should focus on “structurally characterizing these interactions.” They ended by saying, “In summary, we show effects of two classes of secreted XLRS mutations on the structure and stability of retinoschisin to provide further insights into their pathology.”

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