Imagine the USH2A gene as a Rubik’s Cube, hiding the secrets to unlocking a revolution in gene editing and therapy for inherited retinal dystrophies (IRD). In this study, scientists set out to solve the puzzle of USH2A mutations, which are responsible for a majority of IRD cases. Like explorers mapping out uncharted territories, they analyzed a vast genetic spectrum, scouring continents for hotspots of mutation activity. They discovered that mutations in exon 13 were the most prevalent globally, akin to bustling city centers, with varying frequencies across continents. The team identified key exons and mutations that hold the key to solving the puzzles, pinpointing which pieces to correct. And with the help of cutting-edge base editors like ABE and CBE, they found that a remarkable number of single nucleotide variations (SNVs) and mutations can be corrected—the equivalent of fine-tuning specific color combinations on the Rubik’s Cube! Additionally, they unveiled four novel mutations, expanding our understanding of the puzzle even further. This study lays the groundwork for high-efficiency gene editing and therapies that could transform the lives of countless IRD patients. So grab your microscope and delve into this fascinating research to uncover the mysteries of the USH2A Rubik’s Cube!

PurposeMutation in the USH2A gene is the most common cause of inherited retinal dystrophy (IRD), including non-syndromic retinitis pigmentosa (RP) and Usher syndrome II (USH2). Gene editing and therapy targeting USH2A, especially the hotspot region, would benefit a large proportion of IRD patients. In this study, we comprehensively analyzed the genetic spectrum of the USH2A gene, aiming to identify global hot spot mutations in USH2A-related IRDs and differences in hot spot regions across continents.Materials and methodsA retrospective USH2A-related IRD study was conducted, including our IRD cohort, and reported USH2A studies worldwide.ResultsA total of 3,972 mutated USH2A alleles of approximately 1,935 patients were collected from 33 cohort studies worldwide, containing 102 alleles of 51 patients in our IRD cohort. Mutations in exon 13 were the most common, reaching 18.4% globally and a higher frequency of 22% in America, 19.2% in Europe, and a lower 12% in East Asia. Pathogenic mutations that affected 10 of the 72 exons of USH2A, exon 2, exon 13, exon 41–43, exon 50, exon 54, exon 57, exon 61, and exon 63 in total were responsible for half of global USH2A mutant alleles. With base editors including adenine base editor (ABE), cytidine base editor (CBE), and glycosylase base editor (GBE), 76.3% of single nucleotide variations (SNVs) and 58% of all mutations in USH2A are correctable. Meantime, four novel pathogenic mutations were revealed in our IRD cohort, p. (Val1130Cysfs*72), p. (Ala2139fs*14), p. (Gly4139Arg), and p. (Val4166Cysfs*7).ConclusionIn this study, we revealed four novel mutations, expanding the spectrum of USH2A mutations, and importantly presented global hotspot exons and mutations of USH2A as well as the proportion of SNVs that can be restored by different base editors, providing a perspective for exploring high-efficiency and broader-reaching gene editing and gene therapies.

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