PUBLICATION
Disruption of PIKFYVE causes congenital cataract in human and zebrafish
- Authors
- Mei, S., Wu, Y., Wang, Y., Cui, Y., Zhang, M., Zhang, T., Huang, X., Yu, S., Yu, T., Zhao, J.
- ID
- ZDB-PUB-220114-9
- Date
- 2022
- Source
- eLIFE 11: (Journal)
- Registered Authors
- Keywords
- Baf-A1, PIKFYVE, congenital cataract, endosome, gene, genetics, genomics, mutation, zebrafish
- MeSH Terms
-
- Animals
- Cataract/congenital*
- Cataract/genetics*
- Disease Models, Animal
- Exome Sequencing
- HEK293 Cells
- Humans
- Male
- Mutation*
- Phenotype
- Phosphatidylinositol 3-Kinases/genetics*
- Zebrafish/genetics*
- PubMed
- 35023829 Full text @ Elife
Citation
Mei, S., Wu, Y., Wang, Y., Cui, Y., Zhang, M., Zhang, T., Huang, X., Yu, S., Yu, T., Zhao, J. (2022) Disruption of PIKFYVE causes congenital cataract in human and zebrafish. eLIFE. 11:.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping