TY - JOUR TI - Disruption of PIKFYVE causes congenital cataract in human and zebrafish AU - Mei, Shaoyi AU - Wu, Yi AU - Wang, Yan AU - Cui, Yubo AU - Zhang, Miao AU - Zhang, Tong AU - Huang, Xiaosheng AU - Yu, Sejie AU - Yu, Tao AU - Zhao, Jun A2 - Bernstein, Audrey M A2 - Zaidi, Mone VL - 11 PY - 2022 DA - 2022/01/13 SP - e71256 C1 - eLife 2022;11:e71256 DO - 10.7554/eLife.71256 UR - https://doi.org/10.7554/eLife.71256 AB - 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. KW - PIKFYVE KW - congenital cataract KW - gene KW - mutation KW - endosome KW - Baf-A1 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -