International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Acevedo-Arozena A
MRC Mammalian Genetics Unit and UK Mouse Genome Centre

Co-Authors: 1) Chrobot N, 2) Rubinsztein D C, 1) Brown S D
Institutions: 1) MRC Mammalian Genetics Unit and UK Mouse Genome Centre, 2) Cambridge Institute for Medical Research

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by an expanded polyglutamine (PolyQ) repeat in exon 1 of the HD gene. It is characterized by motor, cognitive and psychiatric symptoms, and death ensues about 15 years after disease onset. The number of PolyQ repeats is polymorphic in humans, with normal individuals having up to 37 glutamines, whereas disease is associated with more than 38 repeats. About 70% of the variance of the age-at-onset can be accounted for by its inverse relationship with PolyQ tract length. Although HD is caused by an expanded PolyQ tract, little is known about the downstream effects of the mutation and the possible genetic modifiers that may modulate either the severity or the onset of the disease.

In order to try to identify HD phenotype modifier genes, we have initiated a genetic modifier screen using ENU mutagenesis with a mouse model of HD. In order to select the most suitable model for the ENU screen, we characterized two different widely available transgenic models, B6CBAF1-TgN(HDexon1)61Gpb (R6/1), and B6C3F1-TgN(HD82Gln)81Dbo (N171-82Q). Although the two strains have been the focus of phenotyping in a number of laboratories, we undertook a number of new phenotype analyses on these lines. We studied the mice at several time points using a variety of different tests, including: SHIRPA, rotarod, startle response and prepulse inhibition, locomotor activity, weight loss and fertility. Here, we discuss the results of the characterization of the two strains and elaborate our initial progress with the modifier screen.

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