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The Journal of Neuroscience, March 1, 2003, 23(5):1631

A Mutation in Af4 Is Predicted to Cause Cerebellar Ataxia and Cataracts in the Robotic Mouse

Adrian M. Isaacs^{1, *}, Peter L. Oliver^{1, *}, Emma L. Jones¹, Alexander Jeans¹, Allyson Potter¹, Berit H. Hovik¹, Patrick M. Nolan², Lucie Vizor², Peter Glenister², A. Katharina Simon³, Ian C. Gray⁴, Nigel K. Spurr⁶, Steve D. M. Brown², A. Jackie Hunter⁵, and Kay E. Davies¹

¹ Medical Research Council Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom, ² Medical Research Council Mammalian Genetics Unit, Harwell, Oxon, OX11 0RD, United Kingdom, ³ The Institute for Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom, ⁴ Genetics Research/⁵ Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, Essex CM19 5AW, United Kingdom, and ⁶ Discovery Genetics, GlaxoSmithKline, Research Triangle Park, North Carolina 27709

The robotic mouse is an autosomal dominant mutant that arose from a large-scale chemical mutagenesis program. It has a jerky, ataxic gait and develops adult-onset Purkinje cell loss in the cerebellum in a striking region-specific pattern, as well as cataracts. Genetic and physical mapping of the disease locus led to the identification of a missense mutation in a highly conserved region of Af4, a putative transcription factor that has been previously implicated in leukemogenesis. We demonstrate that Af4 is specifically expressed in Purkinje cells, and we hypothesize that the expression of mutant Af4 leads to neurodegeneration. This function was not identified through knock-out studies, highlighting the power of phenotype-driven mutagenesis in the mouse to identify new pathways involved in neurological disease.

Key words: cerebellum; Purkinje cell; neurodegeneration; ENU mutagenesis; mouse models; positional cloning

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^* A.M.I and P.L.O contributed equally to this work.

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2351631-07$05.00/0

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