Shenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, China.
Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
Elife. 2022 Jan 13;11:e71256. doi: 10.7554/eLife.71256.
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 Rab7Lc3 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.
先天性白内障是一种主要发生在生命的第一个十年内的眼部疾病，是儿童失明的主要原因之一。然而，先天性白内障发病机制的分子机制仍不完全明确。通过对一个患有先天性白内障的中国家庭进行全外显子组测序，我们在 中发现了一个潜在的病理性变异（p.G1943E），该变异位于 PIKFYVE 蛋白的 PIP 激酶结构域。我们证明，PIKFYVE 激酶结构域的杂合/纯合缺失，而不是 在斑马鱼中的过表达，模拟了人类患者的白内障缺陷，这表明单倍不足而非 PIKFYVE 活性的显性抑制导致了这种疾病。对 斑马鱼突变体的表型分析表明，Pikfyve 的缺失导致晶状体细胞中出现异常空泡化（Rab7Lc3 内涵体的积累），用 V-ATP 酶抑制剂巴弗洛霉素 A1（Baf-A1）处理可显著减轻这种空泡化。总之，我们鉴定了 为先天性白内障的一个新的致病基因，并指出了 Baf-A1 治疗 PIKFYVE 缺乏引起的先天性白内障的潜在应用。
