International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Acevedo A 1, Chrobot N 1, Rubinsztein DC 2, Brown SD 1

1 MRC Mammalian Genetics Unit, Harwell, United Kingdom, 2 Cambridge Institute for Medical Research, Cambridge, United Kingdom

Huntington’s disease (HD) is an autosomal dominant, progressive, fatal, neurodegenerative disorder caused by an expanded polyglutamine tract (PolyQ) in exon one of the HD gene. Up to 70% of the variance in age of onset can be accounted for by an inverse relationship with polyQ repeat number. The residual variance is likely to be mediated by environmental and genetic factors (modifiers). In order to identify dominant modifier genes for HD, we have initiated an N-ethyl-N-nitrosourea (ENU) mutagenesis screen with a mouse model of HD. First, we carried out extensive behavioural characterisation of two HD transgenic mouse models (R6/1 and N171-82Q) in order to select the one most suitable strain and to determine baseline phenotypes. Both lines show early signs of disease, including tremors, weight loss and motor deficits. However, N171-82Q strain has more rapid disease progression and better fertility, so it was chosen for the modifier screen. We injected BALB/c males (2 x 100mg/kg ENU), crossed them to N171-82Q carrier females and assessed disease progression in F1s using a variety of simple behavioural analyses (modified from SHIRPA) and weight measurement. Preliminary analyses of the progeny to date has identified several mice carrying potential dominant modifiers that are currently undergoing inheritance testing.

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