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A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degenerative diseases. (Atsushi KUMANOGOH in Nat Commun)
Semaphorin 4A (Sema4A) has an essential role in photoreceptor survival. In humans, mutations in Sema4A are thought to contribute to retinal degenerative diseases.
The authors generate a series of knock-in mouse lines with corresponding mutations (D345H, F350C or R713Q) in the Sema4A gene and find that Sema4AF350C causes retinal degeneration phenotypes.
The F350C mutation results in abnormal localization of the Sema4A protein, leading to impaired endosomal sorting of molecules indispensable for photoreceptor survival. Additionally, protein structural modelling reveals that the side chain of the 350th amino acid is critical to retain the proper protein conformation. Furthermore, Sema4A gene transfer successfully prevents photoreceptor degeneration in Sema4AF350C/F350C and Sema4A-/- mice.
Their findings not only indicate the importance of the Sema4A protein conformation in human and mouse retina homeostasis but also identify a novel therapeutic target for retinal degenerative diseases.
Immunology Frontier Research Center (WPI-IFReC), Osaka University