Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy
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....
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2022.948279/full |
| _version_ | 1818484345299533824 |
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| author | Bing-Nan Su Bing-Nan Su Bing-Nan Su Ren-Juan Shen Ren-Juan Shen Zhuo-Lin Liu Zhuo-Lin Liu Zhuo-Lin Liu Yang Li Yang Li Zi-Bing Jin Zi-Bing Jin Zi-Bing Jin |
| author_facet | Bing-Nan Su Bing-Nan Su Bing-Nan Su Ren-Juan Shen Ren-Juan Shen Zhuo-Lin Liu Zhuo-Lin Liu Zhuo-Lin Liu Yang Li Yang Li Zi-Bing Jin Zi-Bing Jin Zi-Bing Jin |
| author_sort | Bing-Nan Su |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T15:54:06Z |
| format | Article |
| id | doaj.art-24e127b50eca404e933809a233280914 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-10T15:54:06Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-24e127b50eca404e933809a2332809142022-12-22T01:42:41ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652022-08-011410.3389/fnagi.2022.948279948279Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapyBing-Nan Su0Bing-Nan Su1Bing-Nan Su2Ren-Juan Shen3Ren-Juan Shen4Zhuo-Lin Liu5Zhuo-Lin Liu6Zhuo-Lin Liu7Yang Li8Yang Li9Zi-Bing Jin10Zi-Bing Jin11Zi-Bing Jin12School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, ChinaBeijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, ChinaBeijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, ChinaBeijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, ChinaBeijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, ChinaSchool of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, ChinaBeijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, ChinaBeijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, ChinaBeijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, ChinaBeijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, ChinaSchool of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, ChinaBeijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Capital Medical University, Beijing, ChinaBeijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, ChinaPurposeMutation 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.https://www.frontiersin.org/articles/10.3389/fnagi.2022.948279/fullUSH2Amutation hotspotUsher syndromeretinitis pigmentosagene editinginherited retinal dystrophy |
| spellingShingle | Bing-Nan Su Bing-Nan Su Bing-Nan Su Ren-Juan Shen Ren-Juan Shen Zhuo-Lin Liu Zhuo-Lin Liu Zhuo-Lin Liu Yang Li Yang Li Zi-Bing Jin Zi-Bing Jin Zi-Bing Jin Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy Frontiers in Aging Neuroscience USH2A mutation hotspot Usher syndrome retinitis pigmentosa gene editing inherited retinal dystrophy |
| title | Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy |
| title_full | Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy |
| title_fullStr | Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy |
| title_full_unstemmed | Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy |
| title_short | Global spectrum of USH2A mutation in inherited retinal dystrophies: Prompt message for development of base editing therapy |
| title_sort | global spectrum of ush2a mutation in inherited retinal dystrophies prompt message for development of base editing therapy |
| topic | USH2A mutation hotspot Usher syndrome retinitis pigmentosa gene editing inherited retinal dystrophy |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2022.948279/full |
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