title: A mutation in Af4 is predicted to cause cerebellar ataxia and cataracts in the robotic mouse.
abstract: 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.
authors.affiliation: Medical Research Council Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.forename: Emma L
authors.initials: EL
authors.lastname: Jones
authors.forename: Alexander
authors.initials: A
authors.lastname: Jeans
authors.forename: Allyson
authors.initials: A
authors.lastname: Potter
authors.forename: Berit H
authors.initials: BH
authors.lastname: Hovik
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
authors.forename: Lucie
authors.initials: L
authors.lastname: Vizor
authors.forename: Peter
authors.initials: P
authors.lastname: Glenister
authors.forename: A Katharina
authors.initials: AK
authors.lastname: Simon
authors.forename: Ian C
authors.initials: IC
authors.lastname: Gray
authors.forename: Nigel K
authors.initials: NK
authors.lastname: Spurr
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: A Jackie
authors.initials: AJ
authors.lastname: Hunter
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D002386:Cataract / Q000235:genetics*; D002452:Cell Count; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000473:pathology*; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D005799:Genes, Dominant; D051379:Mice; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D020161:Physical Chromosome Mapping; D017354:Point Mutation; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D017386:Sequence Homology, Amino Acid; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
chemical_list: C489900:Aff1 protein, mouse; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins