STUDIES OF A GENETIC MODIFIER OF NUCLEAR CATARACTS

Title STUDIES OF A GENETIC MODIFIER OF NUCLEAR CATARACTS
Author, Co-Author Jing Zeng, Lin Li, Catherine Cheng, Chun-hong Xia, Xiaohua Gong
Topic
Year
2011
Day
Program Number
115296
Room
Amphitheater
Affiliation
University of California Berkeley, School of Optometry
Abstract PURPOSE: Disruption of the a3 connexin gene in 129SvJae(129) and C57BL/6J(B6) mice leads to varying severity of nuclear cataracts, suggesting the presence of a genetic modifier. This work aims to identify a genetic modifier that suppresses nuclear cataracts and to elucidate its underlying molecular basis.

METHODS: Backcrossing and intercrossing a3 knockout (-/-) 129 and a3-/- B6 mice generated offspring that was genotyped for linkage analysis. Lens phenotype was observed by slit lamp examination, and cataract severity was quantitatively measured for light scattering using fiber optic spectrometry. RT-PCR and DNA sequencing were used to evaluate gene candidates. The properties of lens proteins were examined by western blot and morphological changes of lens cells by immunostaining.

RESULTS: Alpha3-/- mice developed mild nuclear cataracts in the B6 strain background and severe dense nuclear cataracts in the 129 strain BACKGROUND: Repeated backcrossing and intercrossing of a3-/- mice in the B6 and 129 strains mapped a genetic suppressor of severe nuclear cataracts to chromosome 7 associated with the D7Mit294 linkage marker. This suppressor was further mapped to a 2 million base pair interval in the B6 strain including D7Mit294. Crossover mice with B6/B6 intervals developed mild cataracts while mice with 129/129 intervals developed severe cataracts. Mice with 129/B6 intervals displayed cataracts of varying severity. The degradation of crystalline proteins was detected in knockout lenses.

CONCLUSIONS: These results indicate a semi-dominant genetic modifier that suppresses the formation of nuclear cataracts in a3-/- mice. Based on a polymorphism search in the coding regions of genes in this interval on chromosome 7, several candidates have been identified for further evaluation. Inhibition of crystallin protein degradation may be related to the function of this genetic modifier.
Affiliation of Co-Authors University of California Berkeley, School of Optometry, University of California Berkeley, School of Optometry, University of California Berkeley, School of Optometry, University of California Berkeley, School of Optometry
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