April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
A DNA Binding Domain Mutation in HSF4 Found in Age- Related Cataract Patients and in Normal Populations Causes Lamellar Cataract in Transgenic Mice
Author Affiliations & Notes
  • Suraj P Bhat
    Ophthalmology, Jules Stein Eye Institute UCLA, Los Angeles, CA
    Brain Research Institute and Molecular Biology Institute, UNiversity of California,, Los Angeles, CA
  • Rajendra K Gangalum
    Ophthalmology, Jules Stein Eye Institute UCLA, Los Angeles, CA
  • Zhe Jing
    Ophthalmology, Jules Stein Eye Institute UCLA, Los Angeles, CA
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5039. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Suraj P Bhat, Rajendra K Gangalum, Zhe Jing; A DNA Binding Domain Mutation in HSF4 Found in Age- Related Cataract Patients and in Normal Populations Causes Lamellar Cataract in Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5039.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract
 
Purpose
 

The most prevalent form of early childhood cataract is associated with dominant mutations in the DNA binding domain of the heat shock transcription Factor4 (HSF4). We have shown that disruption of the DNA binding domain (DBD) of the HSF4 gene recapitulates the dominant human lamellar cataract in mice. Population studies have indicated that a mutation in the exon 3 (R116H) in HSF4 DBD is associated with age-related cataracts. However, this mutation was also found in 3% of the normal population suggesting incomplete penetrance. Since an interference with the DNA binding domain functions of HSF4 lead to dominant phenotypes of Lamellar Cataract formation in humans and in transgenic mice, we wanted to ascertain the phenotype if any, associated with this mutation.

 
Methods
 

We used Red E/T based counter selection system and ‘recombineering’ to modify the large BAC (Bacterial artificial chromosome) DNA molecules to introduce a single base mutation into the exon3 (part of the DNA binding Domain) of the HSF4 gene. Use of BACs for transgenesis allows expression of the transgene that is similar to in vivo patterns of expression. The manipulated HSF4 transgene would produce a mutant HSF4 with DBD containing the human R116H mutation in the developing ocular lens of the transgenic mouse, in a temporally and spatially correct manner.

 
Results
 

Slit lamp examinations of the founders and F1 and F2 generations of animals revealed nuclear opacities similar to the human lamellar cataract phenotypes. This phenotype of dots and/or streaks is confined to a few lamellae or fiber cells within the nucleus of the lens (see Fig 1). Further characterization revealed abnormalities in the secondary fiber cell differentiation attended by varied effects on the expression of a number of genes including the crystallins.

 
Conclusions
 

The cataract recapitulated in the transgenic mice shows characteristic lamellar cataract phenotype both at the morphological as well as at the molecular level. These data suggest that the individuals catalogued under ‘normal population’ carrying the R116H substitution may have escaped clinical examination of the incipient lamellar cataract phenotype. This data will be discussed in light of the complete and incomplete penetrance of cataract phenotypes.

 
 
Human HSF4 R116H cataract in mouse
 
Human HSF4 R116H cataract in mouse
 
Keywords: 445 cataract • 740 transgenics/knock-outs • 739 transcription factors  
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×