Development of a potent embryonic chick lens model for studying congenital cataracts in vivo

Abstract

Congenital cataracts are associated with gene mutations, yet the underlying mechanism remains largely unknown. Here we reported an embryonic chick lens model that closely recapitulates the process of cataract formation. We adopted dominant-negative site mutations that cause congenital cataracts, connexin, Cx50E48K, aquaporin 0, AQP0R33C, αA-crystallin, CRYAA R12C and R54C. The recombinant retroviruses containing these mutants were microinjected into the occlusive lumen of chick lenses at early embryonic development. Cx50E48K expression developed cataracts associated with disorganized nuclei and enlarged extracellular spaces. Expression of AQP0R33C resulted in cortical cataracts, enlarged extracellular spaces and distorted fiber cell organization. αA crystallin mutations distorted lens light transmission and increased crystalline protein aggregation. Together, retroviral expression of congenital mutant genes in embryonic chick lenses closely mimics characteristics of human congenital cataracts. This model will provide an effective, reliable in vivo system to investigate the development and underlying mechanism of cataracts and other genetic diseases.

Anterior Umbilication of Lens in a Family with Congenital Cataracts Associated with a Missense Mutation of MIP Gene

“…The detailed classification basis is as follows: (1) PM1: this variant is located in the first loop outside the transmembrane portion of MIP . The pathogenicity of the variant for congenital cataracts has been verified in the transgenic embryonic chick model [ 18 ]. (2) PM2: this variant is absent in the gnomAD and the 1000 Genomes databases.…”

Connexin Gap Junctions and Hemichannels in Modulating Lens Redox Homeostasis and Oxidative Stress in Cataractogenesis

“…There have been ample studies with regards to the type of cataracts induced by genetic alterations of connexins, including nuclear, nuclear pulverulent, zonular pulverulent, finely granular embryonal, coppock-like and posterior polar [ 3 , 91 , 92 , 93 , 94 ]. Our recent study also provides evidence that connexin channels likely play a role in oxidative stress-related protein aggregation [ 95 ], which offers a potential mechanism in protecting lens proteins after oxidative damage. However, there are limited studies that investigate the role of connexins in the lens in response to oxidative stress in vivo.…”