TY - JOUR
T1 - In vivo lens deficiency of the R49C αA-crystallin mutant
AU - Andley, Usha P.
AU - Reilly, Matthew A.
N1 - Funding Information:
The authors thank Belinda McMahan for help with histology, staining, and immunolabeling. This work was supported by NIH grants EY05681 and EY02687 (Core Grant for Vision Research), and an unrestricted grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness, Inc.
PY - 2010/6
Y1 - 2010/6
N2 - The R49C mutation of αA-crystallin (αA-R49C) causes hereditary cataracts in humans; patients in a four-generation Caucasian family were found be heterozygous for this autosomal dominant mutation. We previously generated knock-in mouse models of this mutation and found that by 2 months of age, heterozygous mutant mice exhibited minor lens defects including reduced protein solubility, altered signaling in epithelial and fiber cells, and aberrant interactions between αA-crystallin and other lens proteins. In contrast, homozygous mutant αA-R49C knock-in mice displayed earlier and more extensive lens defects including small eyes and small lenses at birth, death of epithelial and fiber cells, and the formation of posterior, nuclear, and cortical cataracts in the first month of life. We have extended this study to now show that in αA-R49C homozygous mutant mice, epithelial cells failed to form normal equatorial bow regions and fiber cells continued to die as the mice aged, resulting in a complete loss of lenses and overall eye structure in mice older than 4 months. These results demonstrate that expression of the hereditary R49C mutant of αA-crystallin in vivo is sufficient to adversely affect lens growth, lens cell morphology, and eye function. The death of fiber cells caused by this mutation may ultimately lead to loss of retinal integrity and blindness.
AB - The R49C mutation of αA-crystallin (αA-R49C) causes hereditary cataracts in humans; patients in a four-generation Caucasian family were found be heterozygous for this autosomal dominant mutation. We previously generated knock-in mouse models of this mutation and found that by 2 months of age, heterozygous mutant mice exhibited minor lens defects including reduced protein solubility, altered signaling in epithelial and fiber cells, and aberrant interactions between αA-crystallin and other lens proteins. In contrast, homozygous mutant αA-R49C knock-in mice displayed earlier and more extensive lens defects including small eyes and small lenses at birth, death of epithelial and fiber cells, and the formation of posterior, nuclear, and cortical cataracts in the first month of life. We have extended this study to now show that in αA-R49C homozygous mutant mice, epithelial cells failed to form normal equatorial bow regions and fiber cells continued to die as the mice aged, resulting in a complete loss of lenses and overall eye structure in mice older than 4 months. These results demonstrate that expression of the hereditary R49C mutant of αA-crystallin in vivo is sufficient to adversely affect lens growth, lens cell morphology, and eye function. The death of fiber cells caused by this mutation may ultimately lead to loss of retinal integrity and blindness.
KW - Cataract
KW - Eye
KW - Lens
KW - Mutation
KW - α-crystallin
UR - http://www.scopus.com/inward/record.url?scp=77952784281&partnerID=8YFLogxK
U2 - 10.1016/j.exer.2010.02.009
DO - 10.1016/j.exer.2010.02.009
M3 - Article
C2 - 20188090
AN - SCOPUS:77952784281
SN - 0014-4835
VL - 90
SP - 699
EP - 702
JO - Experimental Eye Research
JF - Experimental Eye Research
IS - 6
ER -