PUBLICATION
A Novel CRYBB2 Splicing Mutation Is Associated With Lens Extracellular Matrix Remodeling and Vascular Alterations in Congenital Cataract
- Authors
- Wei, X., Wang, J., Wang, Y., Zhou, C., Chen, Z., Liu, S., Sun, H., Zhou, B., Zhang, L.
- ID
- ZDB-PUB-260417-23
- Date
- 2026
- Source
- Investigative ophthalmology & visual science 67: 36 (Journal)
- Registered Authors
- Sun, Huaqin, Zhang, Lin
- Keywords
- none
- Datasets
- GEO:GSE333421
- MeSH Terms
- none
- PubMed
- 41989229 Full text @ Invest. Ophthalmol. Vis. Sci.
Citation
Wei, X., Wang, J., Wang, Y., Zhou, C., Chen, Z., Liu, S., Sun, H., Zhou, B., Zhang, L. (2026) A Novel CRYBB2 Splicing Mutation Is Associated With Lens Extracellular Matrix Remodeling and Vascular Alterations in Congenital Cataract. Investigative ophthalmology & visual science. 67:36.
Abstract
Purpose We identify the genetic cause of autosomal dominant congenital cataract in a large family and define how a CRYBB2 splice-site variant perturbs lens development and associated ocular phenotypes.
Methods Whole-exome sequencing and Sanger sequencing were used for variant identification and segregation. Wild-type (WT) or mutant CRYBB2 was expressed in lens epithelial cells to assess splicing and downstream transcriptional changes by RNA sequencing and quantitative reverse transcription PCR (qRT-PCR). Extracellular matrix (ECM) organization and cell-matrix interactions were examined by immunostaining and adhesion assays. In zebrafish, crybb2 disruption was evaluated using lens structural assays, hyaloid vasculature imaging in Tg(flk1:EGFP) larvae, tracer distribution assays, and mRNA rescue. Single-cell RNA sequencing at 48 hours post-fertilization (hpf) was performed to profile lens and vascular populations and infer pathway-level changes.
Results We identified a novel CRYBB2 splice-site variant in affected members of a family with congenital cataract, consistent with an association with the disease in this pedigree. The variant disrupted normal splicing and was associated with altered βB2-crystallin-linked transcriptional programs and ECM homeostasis, including changes in collagen IV/laminin deposition and impaired cell-matrix adhesion. In zebrafish, crybb2 disruption caused lens fiber cell differentiation defects and was accompanied by abnormal hyaloid vascular patterning and altered tracer distribution around the lens; these phenotypes were partially improved by crybb2 mRNA rescue. Single-cell transcriptomic analyses suggested coordinated changes in ECM and junction/adhesion-related pathways across lens and vascular compartments, consistent with a lens-associated, non-cell-autonomous influence on adjacent vasculature.
Conclusions A novel CRYBB2 splice-site mutation is associated with autosomal dominant congenital cataract and disrupts lens homeostasis with accompanying changes in hyaloid vascular remodeling. These findings expand the pathogenic spectrum of CRYBB2 and support a model in which lens abnormalities are associated with altered lens-vascular interactions during development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping