International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


POSTER 229 - MODELS OF NEUROLOGICAL DISEASE IDENTIFIED BY LARGE-SCALE MUTAGENESIS

Mr Adrian Isaacs
Dept of Human Anatomy & Genetics
University of Oxford
South Parks Road
Oxford
OX1 3QX
U.K

Co-Authors: 1)Oliver P, 3)Gray I, 1)Potter A, 1)Masih M, 2)Vizor L, 2)Glenister P, 2)Peters J, 2)Nolan P, 3)Walsh FS, 2)Brown SDM, 3)Spurr N, 3)Hunter AJ, 1)Davies KE1
Institutions: 1) Dept of Human Anatomy & Genetics, University of Oxford, 2) MRC Mammalian Genetics Unit, 3) GlaxoSmithKline

Neurological mouse mutants will have a key role in understanding the pathophysiology of neurological disease. We have identified and characterised potential neurological mutants from the Harwell ENU mutagenesis screen. Two mutant mice with marked resting tremor (Tr-m1H and Tr-m2H), and one mutant with an ataxic, jerky robotic gait (robotic) were analysed. Histopathological analysis revealed hypomyelination in the peripheral nerve of Tr-m1H and Tr-m2H. A rapid mapping strategy incorporating speed backcrosses and high throughput genotyping was used to map the mutants. Robotic mapped to chromosome 5, and no obvious candidate genes are present in the mouse or equivalent human region. A sequence ready BAC contig of the candidate region has now been completed and gene identification and sequencing is in progress. Both tremor mutants were mapped to a region on chromosome 11 containing the peripheral myelin protein 22 gene (Pmp22). Sequence analysis revealed novel point mutations in Pmp22 in both lines. The first mutation H12R, alters the same amino acid as in the severe human peripheral neuropathy Dejerine Sottas syndrome, and Y153Ter in the other line truncates the Pmp22 protein by 7 amino acids. This is the first report of the rapid genetic characterisation of a neurological mutant from a large-scale mutagenesis screen for dominant phenotypes, and validates the use of such protocols to generate desired clinical phenotypes in mouse.


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