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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Published in:eLife 2022-01, Vol.11
Main Authors: Mei, Shaoyi, Wu, Yi, Wang, Yan, Cui, Yubo, Zhang, Miao, Zhang, Tong, Huang, Xiaosheng, Yu, Sejie, Yu, Tao, Zhao, Jun
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Analysis
Animals
Baf-A1
Blindness
Cataract
Cataract - congenital
Cataract - genetics
Cataracts
congenital cataract
Congenital diseases
Danio rerio
Disease Models, Animal
endosome
Families & family life
gene
Genes
Genetic disorders
Genetics and Genomics
H+-transporting ATPase
Haploinsufficiency
HEK293 Cells
Humans
Kinases
Male
Males
Molecular modelling
Mutation
Phenotype
Phosphatidylinositol 3-Kinases - genetics
PIKFYVE
Proteins
Surgery
Visual impairment
Whole Exome Sequencing
Zebrafish - genetics
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Summary: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 , 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 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 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 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.71256