scholarly journals Mutations in PIKFYVE cause autosomal dominant congenital cataract

2021 ◽  
Author(s):  
Shaoyi Mei ◽  
Yi Wu ◽  
Yan Wang ◽  
Yubo Cui ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Chinese Family ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Causative Gene ◽  
Whole Exome ◽  
Autosomal Dominant Congenital Cataract

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.

scholarly journals Disruption of PIKFYVE causes congenital cataract in human and zebrafish

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Shaoyi Mei ◽  
Yi Wu ◽  
Yan Wang ◽  
Yubo Cui ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Molecular Mechanisms ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Chinese Family ◽  
Bafilomycin A1 ◽  
Atpase Inhibitor ◽  
Causative Gene ◽  
Whole Exome ◽  
Pathological Variant

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.

scholarly journals A novel CRYGD mutation (p.Trp43Arg) causing autosomal dominant congenital cataract in a Chinese family

2010 ◽  
Vol 32 (1) ◽  
pp. E1939-E1947 ◽  
Author(s):  
Binbin Wang ◽  
Changhong Yu ◽  
Yi-Bo Xi ◽  
Hong-Chen Cai ◽  
Jing Wang ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Chinese Family ◽  
Autosomal Dominant Congenital Cataract

scholarly journals Whole Exome Sequencing Reveals Novel and Recurrent Disease-Causing Variants in Lens Specific Gap Junctional Protein Encoding Genes Causing Congenital Cataract

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 512
Author(s):  
Vanita Berry ◽  
Alex Ionides ◽  
Nikolas Pontikos ◽  
Ismail Moghul ◽  
Anthony T. Moore ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Sequence Variant ◽  
Whole Exome ◽  
Protein Encoding ◽  
Novel Variant ◽  
Junctional Protein ◽  
Autosomal Dominant Congenital Cataract ◽  
Gap Junctional ◽  
Encoding Genes

Pediatric cataract is clinically and genetically heterogeneous and is the most common cause of childhood blindness worldwide. In this study, we aimed to identify disease-causing variants in three large British families and one isolated case with autosomal dominant congenital cataract, using whole exome sequencing. We identified four different heterozygous variants, three in the large families and one in the isolated case. Family A, with a novel missense variant (c.178G>C, p.Gly60Arg) in GJA8 with lamellar cataract; family B, with a recurrent variant in GJA8 (c.262C>T, p.Pro88Ser) associated with nuclear cataract; and family C, with a novel variant in GJA3 (c.771dupC, p.Ser258GlnfsTer68) causing a lamellar phenotype. Individual D had a novel variant in GJA3 (c.82G>T, p.Val28Leu) associated with congenital cataract. Each sequence variant was found to co-segregate with disease. Here, we report three novel and one recurrent disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract. Our study further extends the mutation spectrum of these genes and further facilitates clinical diagnosis. A recurrent p.P88S variant in GJA8 causing isolated nuclear cataract provides evidence of further phenotypic heterogeneity associated with this variant.

scholarly journals A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal dominant congenital cataract in a large Chinese family

2008 ◽  
Vol 29 (5) ◽  
pp. 769-769 ◽  
Author(s):  
Feng Gu ◽  
Weixiao Luo ◽  
Xin Li ◽  
Zhuoqun Wang ◽  
Shuang Lu ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Chinese Family ◽  
Autosomal Dominant Congenital Cataract

scholarly journals A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Zhou ◽  
Yaru Zhai ◽  
Lulin Huang ◽  
Bo Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Whole Exome ◽  
Causal Mutation ◽  
Control Samples

Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499T<G (p.E167X) in CRYBB2 gene was found. And the results showed that the mutation cosegregated with the disease phenotype in the family and was absolutely absent in 1000 ethnicity-matched control samples. Thus, the heterozygous mutation c.499T<G (p.E167X) in CRYBB2 was the causal mutation responsible for this ADCC family. In conclusion, our findings revealed a novel stopgain mutation c.499T<G (p.E167X) in the exon 6 of CRYBB2 which expanded the mutation spectrum of CRYBB2 in Chinese congenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract.

scholarly journals Partial duplication of the CRYBB1-CRYBA4 locus is associated with autosomal dominant congenital cataract

2016 ◽  
Author(s):  
Owen M. Siggs ◽  
Shari Javadiyan ◽  
Shiwani Sharma ◽  
Emmanuelle Souzeau ◽  
Karen M. Lower ◽  
...  
Keyword(s):  
Conflict Of Interest ◽  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Copy Number Variant ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Autosomal Dominant Congenital Cataract ◽  
Variant Analysis ◽  
Short Indels

AbstractCongenital cataract is a rare but severe paediatric visual impediment, often caused by variants in one of several crystallin genes that produce the bulk of structural proteins in lens. Here we describe a pedigree with autosomal dominant isolated congenital cataract and linkage to the crystallin gene cluster on chromosome 22. No rare single nucleotide variants or short indels were identified by whole-exome sequencing, yet copy number variant analysis revealed a duplication spanning both CRYBB1 and CRYBA4. While the CRYBA4 duplication was complete, the CRYBB1 duplication was not, with the duplicated CRYBB1 product predicted to create a gain of function allele. This association suggests a new genetic mechanism for the development of isolated congenital cataract.Grant informationSupported by the National Health and Medical Research CouncilConflict of interestthe authors declare no conflict of interest.

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