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E. L. Hassemer, L. Jackson, R. R. Dubielzig, B. Chang, D. J. Sidjanin; Mapping and Cloning of the Waved With Open Eyes (woe) Locus. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5862.
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© ARVO (1962-2015); The Authors (2016-present)
Waved with open eyes (woe) is an autosomal recessive mouse mutant that arose spontaneously on the C57BL/6J X DBA/2J F1 background. Phenotypically at 3 weeks of age, the woe mice show a wavy coat, microphthalmia/anophthalmia, lymphoplasmacytic blepharitis, stromal keratitis with anterior synechiae, anterior lens capsule folds, nuclear cataract, segmental lymphoplasmacytic inflammation of the meibomian gland with atrophy and abnormal melanin distribution. The purpose of this study is to identify the mutation responsible for the woe phenotype.
The woe mice were backcrossed to generate 138 F2 progeny which were phenotypically evaluated at three weeks of age. Genomic DNA was isolated from the collected F2 progeny spleens and mapped with microsatellite markers. For candidate gene evaluation, primers were designed approximately 50 bp away from intron/exon junctions.
Genome wide scan identified linkage between the woe locus and microsatellite markers on the proximal arm of mouse chromosome 12. No recombinants were identified between the woe phenotype and D12Mit12. Evaluation of the woe critical region identified Adam17 as a candidate gene. The sequence analysis revealed C794T substitution that leads to Thr265Met change in the metalloproteinase domain of Adam17. We evaluated C57BL/6J, DBA/2J and C3H/HeJ strains and all show the C794 allele suggesting that the identified C794T substitution is not a polymorphism.
The woe mouse shows severe ophthalmological defects. The genetic analysis identified a Thr265Met substitution in an evolutionarily highly conserved metalloproteinase domain of Adam17. The role of Adam17 is in shedding the soluble forms of TNF-α, TGF-α and other proteins from their membrane-bound precursors. Currently, we are evaluating the expression and the role of Adam17 in eye development in both wild-type and woe mice.
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