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Jochen Graw, Oliver Puk, Susanne Weber, Sibylle Wagner, Frank Thiele, Gerhard Przemeck, Martin Hrabé de Angelis; Bmpr1b Splice Site Mutation Leads To Optic Nerve Head Degeneration In The Mouse. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1534.
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Mutations affecting the optic nerve head can be identified by funduscopy or more precisely by optical coherence tomography (OCT). During the last years, we identified several mutants with optic nerve phenotypes (Fun6, Aey69, Ali30) both during ENU screen and within the German Mouse Clinic (GMC). Here we describe the Ali30 mutant being characterized within the framework of the GMC.
The mutation was mapped by a SNP-based linkage analysis and candidate genes were sequenced. The eyes of the mutants were analyzed by in-situ hybridization and immunohistochemistry. Functional testes included electroretinography and the virtual drum.
The underlying mutation affects the Bmpr1b gene, particularly by a T->G transversion in the splice donor site of exon 10. The mutants show irregular forelimb and hindlimb morphology, brachydactyly, irregular cartilage development and alterations in the reproductive system. The lens is clear, but in homozygous mutants, an enlarged optic disc was observed. The eyes are slightly larger, which is mainly due to an increased aqueous humor. Electroretinography demonstrated a more rapid decline of the b-wave indicating a less efficient transmission of electric stimuli within the retina. Moreover, homozygous mutant mice show also almost no response to moving stripes as compared to the wild type mice. Histological analysis indicated dramatic changes in the optic nerve head. Analysis of the embryonic development of the eye showed a rather posterior expression area of Pax6, and concomitantly, Pax2 expression (which is regularly expressed at embryonic day 11.5) and the presence of Epha4 are reduced. In adults, the optic nerve head degenerates progressively. This is due to a reduced phosphorylation of the Bmpr1b downstream target, Smad1, and an increased apoptosis.
Compared to the already described Bmpr1b-konockout mice, the Ali30 mutant represents a rather hypomorphic allele.
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