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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.

Type

Journal article

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Date

03/2003

Volume

23

Pages

1631 - 1637

Addresses

Medical Research Council Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.

Keywords

Cerebellum, Purkinje Cells, Thymus Gland, Animals, Mice, Mice, Neurologic Mutants, Cerebellar Ataxia, Cataract, Disease Models, Animal, Disease Progression, DNA-Binding Proteins, Nuclear Proteins, Antigens, CD, Flow Cytometry, Cell Count, Physical Chromosome Mapping, Organ Specificity, Mutagenesis, Amino Acid Sequence, Conserved Sequence, Sequence Homology, Amino Acid, Genes, Dominant, Point Mutation, Molecular Sequence Data