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Mouse models to identify novel disease genes.

Vortrag: 6. Pro-Retina Research Colloquium Potsdam: Retinal Degeneration, 9-10 April 2010, Potsdam, Germany. (2010)
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Purpose: To identify novel disease genes responsible for eye disorders in the mouse. Methods: Male C3HeB/FeJ or C57BL/6J mice were treated with N-ethyl-N-nitrosourea (ENU) and mated with untreated females; the offspring were screened for gross morphological alterations including the eye by manual inspection or for ocular disorders by slit lamp, funduscopy and laser interference biometry (LIB). In confirmed mutant lines, we performed a genome-wide linkage analysis and sequenced positional candidate genes. The second approach characterizes already existing mouse mutants by comprehensive phenotyping within the framework of the German Mouse Clinic (GMC). Results: In the ongoing ENU screen, a total of 1700 C57BL/6J mice have been screened. The most efficient screening method was LIB leading to 12 new mouse mutant lines. 3 lines were mapped, and their underlying mutations are identified: Aca23 suffers from a small cornea and an enlarged anterior chamber; the mutation affects Col8a2, which is known to be involved in corneal disorders. Aca12 is characterized by a small lens and shorter axis; the underlying mutation affects Fgf9, which was not yet reported to be affected in eye disorders. Aca30 has a similar phenotype like Aca12, but the underlying mutation affects the Cryba2 gene; there is no mutation reported neither in mice nor in humans. Screening by funduscopy revealed 2 confirmed mutant lines. Fun6 mutants are characterized by optic disc anomalies; the mutation is localized on chromosome 19. Fun22 mutants show a pale spotted fundus. Among the C3HeB/FeJ-treated mice, Aey69 mutants are suffering from anophthalmia/ microphthalmia; the mutation is mapped to chromosome 3. The ocular phenotype of the Ali30 mutant was picked up in the GMC: it is suffering from optic nerve head dysplasia and characterized by a splice-site mutation in the Bmpr1b gene, which was not yet reported to be responsible for ocular disorders. Conclusions: The outcome of screening methods depends not only on the numbers of screened animals, but also on the applied screening methods. Additional screening techniques resulting in quantitative data (Scheimpflug imaging for lens opacities) or in higher resolution (like optical coherence tomography for retinal disorders) are necessary. Subtle phenotypes in young animals might be important indicators for significant age-related disorders.
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Publication type Other: Lecture
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