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Duska Sidjanin, Bo Chang, Ryan Liegel; A mutation in a RABGAP is responsible for cataracts in the blind-sterile (bs) mouse and Warburg micro syndrome patients. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1265. doi: https://doi.org/.
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The blind-sterile (bs) locus is a recessive mouse mutation that arose spontaneously on the AKR/J background. bs mice exhibit congenital cataracts and male sterility. Previous studies mapped the bs locus to the distal end of Chr. 2. The goals of this study were to identify the gene containing the mutation responsible for cataracts in the bs mouse. In addition, the goal was to determine if mutations in the same gene contribute to human cataracts.
Clinical evaluation was done with a slit-lamp following mydriasis. bs homozygote females were outcrossed to the CAST/EiJ males followed by F1 (bs X CAST/EiJ) intercross matings to generate 1177 F2 progeny. At three weeks of age, the F2 progeny were evaluated for cataracts, then euthanized and tissues were collected for genetic and H&E analysis. Mapping was done using microsatellite and SNP markers. Candidate gene analyses were performed using exon scanning and cDNA sequencing.
Mapping analysis assigned the bs locus to a 415 kb critical region containing 16 candidate genes. Sequence analysis identified a 12 bp deletion in a gene that encodes a member of the RABGAP family of proteins. The 12-bp deletion resulted in an in-frame deletion of 4 amino acids and an additional amino acid substitution within an evolutionarily conserved active domain. Based on the function of the gene as well as the bs phenotype, we hypothesized that mutations in the same gene may be contributing to the Warburg micro syndrome. The analysis identified 4 different nonsense mutations in the same RABGAP gene in 4 unrelated Warburg micro syndrome patients.
We've identified a mutation in a RABGAP gene contributing to the formation of cataracts in the bs mouse and Warburg micro syndrome patients. RABGAPs play essential roles in regulating RAB proteins via GTPase hydrolysis and thereby switching them from an active GTP-bound form to an inactive GDP-bound form. RAB proteins play an essential role in vesicular trafficking. Currently, we are investigating the role of this RABGAP for the lens development as well as molecular mechanisms contributing to cataractogenesis in bs mice as well as in Warburg micro syndrome patients.
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