2. Academic Validation
  3. Disruption of PIKFYVE causes congenital cataract in human and zebrafish

Disruption of PIKFYVE causes congenital cataract in human and zebrafish

  • Elife. 2022 Jan 13;11:e71256. doi: 10.7554/eLife.71256.
Shaoyi Mei  # 1,  Yi Wu  # 2,  Yan Wang  # 3,  Yubo Cui 4,  Miao Zhang 1,  Tong Zhang 1,  Xiaosheng Huang 1,  Sejie Yu 4,  Tao Yu 2,  Jun Zhao 4
Affiliations

Affiliations

  • 1 Shenzhen Eye Institute, Shenzhen Eye Hospital Affiliated to Jinan University, Shenzhen, China.
  • 2 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.
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Ophthalmology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The first Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
  • # Contributed equally.
PMID: 35023829 DOI: 10.7554/eLife.71256
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.

Keywords

Baf-A1; PIKFYVE; congenital cataract; endosome; gene; genetics; genomics; mutation; zebrafish.

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