Purchase this article with an account.
Suraj P. Bhat, Rajendra K. Gangalum, Zhe Jing, Sophie X. Deng, Josh Lee; Recreation of Human Lamellar/Marner's cataract in Mice Employing Bacterial Artificial Chromosome (BAC) Transgenesis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2085.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Early Childhood cataract has debilitating consequences for neural development. Lamellar/Marner’s cataract, the most prevalent form of early childhood cataract has been linked to mutations in the DNA binding domain (DBD) of heat shock transcription factor 4 (HSF4). In order to understand the biogenesis of this cataract we have recreated this pathology in the mouse.
A mutation in a transcriptional factor is subtle and excludes direct interference in the status of a structural protein. Using BAC transgenesis, which assures correct temporal and spatial expression, we have engineered mutations into the HSF4 DBD using two approaches: (a) Known mutations (L115P and R117H) were independently introduced into mouse HSF4 transgene and (b) A novel approach in which eGFP (enhanced Green Fluorescent Protein) coding sequences were used to disrupt the DBD of the HSF4 transgene.
We have recreated the human Lamellar/Marner’s cataract phenotype in the mouse. These phenotypes presented 1. Punctuate discrete opacity within the primary nucleus associated with curved opacification, possibly in the same lamellar plane and/or 2. Multiple discrete opacities, mostly in the primary nucleus, located in different lamellae; in some cases these ‘dots’ /opacities could be connected within an opacified fiber. Slit lamp pictures of transgenic (Tg) founder, WT, Human Lamellar cataract (J Med Genet 37:481-488, 2000), and Tg F1 (a composite of six images taken at different depths) are shown here. We also followed the expression of the hybrid HSF4-eGFP gene in various tissues in the transgenic animals, which point to molecular mechanism of the appearance of the phenotype.
Cataracts generated in this transgenic model appear as dots of opacity and are confined to the nucleus of the mouse lens. The cataract is subtle and confined just like in the human Lamellar/Marners cataract providing for the first time a mouse paradigm of a human pathology that would otherwise be impossible to investigate.
This PDF is available to Subscribers Only