April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Roles of Multiple Genetic Factors in Nuclear Cataracts
Author Affiliations & Notes
  • X. Gong
    Vision Sci School of Optometry,
    University of California, Berkeley, Berkeley, California
  • L. Li
    School of Optometry, Univ of California - Berkeley, Berkeley, California
  • C. Cheng
    University of California, Berkeley, Berkeley, California
  • T. W. White
    Physiology & Biophysics, State Univ of NY-Stony Brook, Stony Brook, New York
  • B. Chang
    The Jackson Laboratory, Bar Harbor, Maine
  • C.-H. Xia
    School of Optometry,
    University of California, Berkeley, Berkeley, California
  • Footnotes
    Commercial Relationships  X. Gong, None; L. Li, None; C. Cheng, None; T.W. White, None; B. Chang, None; C.-H. Xia, None.
  • Footnotes
    Support  NIH Grant EY013849
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 1596. doi:
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      X. Gong, L. Li, C. Cheng, T. W. White, B. Chang, C.-H. Xia; Roles of Multiple Genetic Factors in Nuclear Cataracts. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1596.

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

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Purpose: : To study the molecular basis of nuclear cataracts linked to the mutations of connexin and gammaB-crystallin genes and to identify how other genes regulate the nuclear cataract formation in alpha3 connexin (Gja3 or Cx46) knockout mice.

Methods: : Genetic approaches with various linkage markers were used to localize new genetic factors that regulate the severity of nuclear cataracts associated with connexin mutant mice at various genetic or strain backgrounds. Variance in lens opacities among different mutant mice was quantitatively measured by a fiber optic spectrometer. Cellular and biochemical methods were used to determine lens protein changes in nuclear cataracts that are influenced by the dosage of different gene alleles.

Results: : Increased alpha3 connexin proteins of a knock-in allele, a8(Kia3), suppressed severe nuclear cataracts caused by the gammaB-crystallin-S11R mutation. Two alleles of a8(Kia3) fully prevented dense nuclear opacities while one allele delayed the development of nuclear opacity. The cataract prevention was correlated with the maintenance of normal calcium level and actin filaments as well as the suppression of various pathological processes including crystallin degradation and fiber cell degeneration. In addition, the severity of nuclear cataracts was variable among alpha3 knockout at mixed 129 and B6 strain backgrounds. Presence of a dominant suppressor was confirmed on B6 chromosome 7. Examining multiple linkage markers with 129/B6 crossing over alpha3 knockout mice, we located this dominant suppressor in a region close proximity to the marker D7Mit115. The light scattering measurement suggested that this suppressor displayed a dosage dependent inhibition of the nuclear cataracts.

Conclusions: : This work demonstrates that enhanced or reduced gap junction communication is one of multiple genetic components in prevention or promotion of nuclear cataracts. Elevated alpha3 connexin enhances lens cell-cell communication that likely prevents calcium level elevation to inhibit the calpain-mediated degradation of crystallins. The dominant suppressor is likely related to the regulation of the solubility and/or stability of crystallins that is known to be associated with nuclear cataracts of alpha3 knockout mice. The gene identity of this dominant suppressor and the mechanism for how alpha3 connexin leads to a dosage-dependent inhibition of gammaB-S11R nuclear cataract need further investigation.

Keywords: cell-cell communication • cataract • crystallins 

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