Disruption of PIKFYVE causes congenital cataract in human and zebrafish

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.

Autophagic lysosome reformation in health and disease

“…This includes Yunis-Varón Syndrome [ 167 , 168 ], amyotrophic lateral sclerosis (ALS) [ 169 ], Charcot Marie-tooth 4J (CMT4J) [ 170 ], familial epilepsy [ 171 ], Parkinsonism [ 172 ], and a pediatric neurological disorder called striatonigral degeneration [ 161 , 173 , 174 ]. PIKFYVE mutations cause hereditary ocular disorders including François-Neetens mouchetée fleck corneal dystrophy [ 175 ] and congenital cataracts [ 176 ]. There are recent reports that PtdIns(3,5)P 2 may regulate ALR via the effector MCOLN1/TRPML1 [ 31 ], or possibly via effects on MTOR reactivation [ 177 ].…”

Roles of PIKfyve in multiple cellular pathways

“…Defects in the PIKfyve complex are linked to human diseases, especially those of the nervous system [ 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], although the underlying molecular mechanisms are not clear. For example, mutations in Fig4 predicted to have a modest effect in the regulation of PI(3,5) 2 are linked to Charcot-Marie-Tooth syndrome (CMT4J), a peripheral neuropathy, as well as some cases of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).…”

Effects of Tcte1 knockout on energy chain transportation and spermatogenesis: implications for male infertility

“…P1/P2 protamines, Pde8b , Trim28 , Tcfl5 ), and to the other diseases (i.e. PIKFYVE in cataract, NFIA , SCN1A in neurological or epilepsy disturbances, KLF1 in hemoglobin persistence, NR5A2 in pancreatic cancer), seem to confirm that the severity of the phenotype depends on the gene expression level ( Jodar and Oliva, 2014 ; Tan et al , 2020 ; Leal et al , 2021 ; Sandhu et al , 2021 ; Heshusius et al , 2022 ; Mei et al , 2022 ; Ogura et al , 2022 ; Valassina et al , 2022 ; Xu et al , 2022 ). We have documented variable phenotypes for a novel TCTE1 variant c.374T>G (p.Ile125Arg) that has been documented in seven males, with azoospermia, cryptozoospermia, or severe oligoasthenozoospermia.…”