Human Molecular Genetics, 2000, Vol. 9, No. 12 1865-1871
© 2000 Oxford University Press
Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy
Department of Human Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK, 1Department of Neuroscience, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK, 2MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, Oxon OX11 ORD, UK, 3Department of Biotechnology and Genetics, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK, 4Centre for Cutaneous Research, Queen Mary and Westfield College, London E1 4NS, UK, 5Department of Neurogenetics, Imperial College, London SW7 2AZ, UK and 6Department of Histopathology, Queen Mary and Westfield College, London E1 4NS, UK
Mouse mutants have a key role in discerning mammalian gene function and modelling human disease; however, at present mutants exist for only 1–2% of all mouse genes. In order to address this phenotype gap, we have embarked on a genome-wide, phenotype-driven, large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant mutations of clinical and pharmacological interest in the mouse. Here we describe the identification of two similar neurological phenotypes and determination of the underlying mutations using a novel rapid mapping strategy incorporating speed back-crosses and high throughput genotyping. Two mutant mice were identified with marked resting tremor and further characterized using the SHIRPA behavioural and functional assessment protocol. Back-cross animals were generated using in vitro fertilization and genome scans performed utilizing DNA pools derived from multiple mutant mice. Both 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 mutant truncates the Pmp22 protein by seven amino acids. Histological analysis of both lines revealed hypomyelination of peripheral nerves. This is the first report of the generation of a clinically relevant neurological mutant and its rapid genetic characterization from a large-scale mutagenesis screen for dominant phenotypes in the mouse, and validates the use of large-scale screens to generate desired clinical phenotypes in mice.
+ To whom correspondence should be addressed. Tel: +44 1279 627225; Fax: +44 1279 622500; Email: ian_gray-1@sbphrd.com
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