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bioRxiv · 10.1101/2021.06.25.449865

Mutations in PIKFYVE cause autosomal dominant congenital cataract

Mei, S.·Wu, Y.·Wang, Y.·Cui, Y.·Zhang, M.·Zhang, T.·Huang, X.·Yu, S.·Yu, T.·Zhao, J.
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Abstract

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting 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 demonstrated the potential application of Baf-A1 in treatment of congenital cataract.

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Mei, S., Wu, Y., Wang, Y., Cui, Y., Zhang, M., Zhang, T., Huang, X., Yu, S., Yu, T., Zhao, J.. 2021-06-26. Mutations in PIKFYVE cause autosomal dominant congenital cataract. https://doi.org/10.1101/2021.06.25.449865

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