Disruption of PIKFYVE causes congenital cataract in human and zebrafish
Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. However, the molecular mechanisms underlying the pathogenesis of congenital cataract remain incompletely defined. Through whole-exome sequencing of a...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/71256 |
| _version_ | 1811199437416955904 |
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| author | Shaoyi Mei Yi Wu Yan Wang Yubo Cui Miao Zhang Tong Zhang Xiaosheng Huang Sejie Yu Tao Yu Jun Zhao |
| author_facet | Shaoyi Mei Yi Wu Yan Wang Yubo Cui Miao Zhang Tong Zhang Xiaosheng Huang Sejie Yu Tao Yu Jun Zhao |
| author_sort | Shaoyi Mei |
| collection | DOAJ |
| description | Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. However, the molecular mechanisms underlying the pathogenesis of congenital cataract remain incompletely defined. Through whole-exome sequencing of a Chinese family with congenital cataract, we identified a potential pathological variant (p.G1943E) in PIKFYVE, which is located in the PIP kinase domain of the PIKFYVE protein. We demonstrated that heterozygous/homozygous disruption of PIKFYVE kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKFYVE activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and pinpointed the potential application of Baf-A1 for the treatment of congenital cataract caused by PIKFYVE deficiency. |
| first_indexed | 2024-04-12T01:48:05Z |
| format | Article |
| id | doaj.art-3c47a988f1ea4bb29e233ff5d66e6597 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:48:05Z |
| publishDate | 2022-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3c47a988f1ea4bb29e233ff5d66e65972022-12-22T03:53:01ZengeLife Sciences Publications LtdeLife2050-084X2022-01-011110.7554/eLife.71256Disruption of PIKFYVE causes congenital cataract in human and zebrafishShaoyi Mei0https://orcid.org/0000-0002-0684-3821Yi Wu1https://orcid.org/0000-0002-9907-9403Yan Wang2Yubo Cui3Miao Zhang4Tong Zhang5Xiaosheng Huang6Sejie Yu7Tao Yu8https://orcid.org/0000-0001-6017-4852Jun Zhao9https://orcid.org/0000-0002-7285-5812Shenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, ChinaShenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, ChinaDepartment of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The first Affiliated Hospital, Southern University of Science and Technology), Shenzhen, ChinaShenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, ChinaShenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, ChinaShenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, ChinaDepartment of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The first Affiliated Hospital, Southern University of Science and Technology), Shenzhen, ChinaShenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, ChinaDepartment of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The first Affiliated Hospital, Southern University of Science and Technology), Shenzhen, ChinaCongenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. However, the molecular mechanisms underlying the pathogenesis of congenital cataract remain incompletely defined. Through whole-exome sequencing of a Chinese family with congenital cataract, we identified a potential pathological variant (p.G1943E) in PIKFYVE, which is located in the PIP kinase domain of the PIKFYVE protein. We demonstrated that heterozygous/homozygous disruption of PIKFYVE kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKFYVE activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and pinpointed the potential application of Baf-A1 for the treatment of congenital cataract caused by PIKFYVE deficiency.https://elifesciences.org/articles/71256PIKFYVEcongenital cataractgenemutationendosomeBaf-A1 |
| spellingShingle | Shaoyi Mei Yi Wu Yan Wang Yubo Cui Miao Zhang Tong Zhang Xiaosheng Huang Sejie Yu Tao Yu Jun Zhao Disruption of PIKFYVE causes congenital cataract in human and zebrafish eLife PIKFYVE congenital cataract gene mutation endosome Baf-A1 |
| title | Disruption of PIKFYVE causes congenital cataract in human and zebrafish |
| title_full | Disruption of PIKFYVE causes congenital cataract in human and zebrafish |
| title_fullStr | Disruption of PIKFYVE causes congenital cataract in human and zebrafish |
| title_full_unstemmed | Disruption of PIKFYVE causes congenital cataract in human and zebrafish |
| title_short | Disruption of PIKFYVE causes congenital cataract in human and zebrafish |
| title_sort | disruption of pikfyve causes congenital cataract in human and zebrafish |
| topic | PIKFYVE congenital cataract gene mutation endosome Baf-A1 |
| url | https://elifesciences.org/articles/71256 |
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