Journal Article

Identification of two new <i>Pmp22</i> mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy

Adrian M. Isaacs, Kay E. Davies, A. Jackie Hunter, Patrick M. Nolan, Lucie Vizor, Jo Peters, Davina G. Gale, David P. Kelsell, Ian D. Latham, Jennifer M. Chase, Elizabeth M.C. Fisher, Mark M. Bouzyk, Allyson Potter, Mohan Masih, Frank S. Walsh, Matthew A. Sims, Kim E. Doncaster, Claire A. Parsons, Jo Martin, Steven D.M. Brown, Sohaila Rastan, Nigel K. Spurr and Ian C. Gray

in Human Molecular Genetics

Volume 9, issue 12, pages 1865-1871
Published in print July 2000 | ISSN: 0964-6906
Published online July 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.12.1865
Identification of two new Pmp22 mouse mutants using large-scale mutagenesis and a novel rapid mapping strategy

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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.

Journal Article.  4812 words.  Illustrated.

Subjects: Genetics and Genomics

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