Genetic background modulates the phenotype of a mouse model of dyt1 dystonia

Lauren M. Tanabe, Caitlin Martin, William T. Dauer

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

DYT1 dystonia is a debilitating neurological disease characterized by involuntary twisting movements. The disease is caused by an in-frame deletion (GAG, "ΔE") mutation in the TOR1A gene that encodes the torsinA protein. Intriguingly, only 30% of mutation carriers exhibit motor symptoms despite the fact that functional brain imaging studies show abnormal brain metabolism in all carriers. Because genetic modifiers may be a determinant of this reduced penetrance, we examined the genetic contribution of three different inbred strains of mice on the DYT1 mutation in animals that are homozygous (Tor1a ΔE/ΔE) or heterozygous (Tor1a ΔE/+; disease state) for the disease-causing ΔE mutation. We find that the DBA/2J, C57BL/6J, and CD1-ICR contribution of genes significantly alter lifespan in Tor1a ΔE/ΔE mice, which die during the first few days of life on the 129S6/SvEvTac (129) background. The C57BL/6J (B6) strain significantly decreases life expectancy of Tor1a ΔE/ΔE animals but, like 129S6/SvEvTac Tor1a ΔE/+ mice, congenic C57BL/6J Tor1a ΔE/+ mice do not exhibit any motor abnormalities. In contrast, the DBA/2J (D2) strain significantly increases life expectancy. This effect was not present in congenic DBA/2J Tor1a ΔE/ΔE mice, indicating that the extended lifespan of F2 129/D2 mice was due to a combination of homozygous and heterozygous allelic effects. Our observations suggest that genetic modifiers may alter the penetrance of the ΔE mutation, and that mapping these modifiers may provide fresh insight into the torsinA molecular pathway.

Original languageEnglish (US)
Article numbere32245
JournalPloS one
Volume7
Issue number2
DOIs
StatePublished - Feb 29 2012
Externally publishedYes

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DNA Mutational Analysis
Postural Balance
Genetic Crosses
animal disease models
Animal Disease Models
Animal Behavior
Inbred DBA Mouse
molecular chaperones
Molecular Chaperones
Dystonia
Genetic Models
Inbred C57BL Mouse
animal behavior
genetic background
animal models
Genotype
Phenotype
phenotype
Mutation
modifiers (genes)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Genetic background modulates the phenotype of a mouse model of dyt1 dystonia. / Tanabe, Lauren M.; Martin, Caitlin; Dauer, William T.

In: PloS one, Vol. 7, No. 2, e32245, 29.02.2012.

Research output: Contribution to journalArticle

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