These clinical studies highlight that the apparent penetrance of a mutation depends greatly on the phenotype being assessed, and demonstrate that all DE mutation NSC 632839 carriers have abnormally functioning brains. The factors that determine conversion from sub-clinical ����endophenotype���� to overt disease remain unknown. Similarly, nearly all animals harboring monogenic mutations show significant phenotypic variability, likely due to multiple intermingling factors such as environment, allelic heterogeneity and stochastic effects, as well as the presence of modifier genes. Indeed, a focus on the effect of this ����genetic background noise���� is emerging in an effort to understand what makes some individuals more susceptible than others to certain disease-causing mutations. The features of DYT1 dystonia suggest that this disease may be an excellent model system in which to examine these issues. Possible genetic modifiers of the torsinA pathway include torsinB, which has redundant functions, and other torsinA-interacting proteins, including LAP1, LULL1 and printor. Importantly, identifying factors that modulate DE-torsinA phenotypes has the potential not only to provide insight into disease mechanism, but also may suggest alternative strategies for disease treatment and prevention. Given the many factors that can modulate disease phenotypes, it can be exceedingly difficult to model diseases with limited penetrance, such as DYT1 dystonia. To date, etiologic mouse models of DYT1 dystonia do not have any obvious dystonic features or evidence of pathology such as neuronal loss, including transgenic mice expressing human mutant torsinA, and heterozygous knock-in mice in which the DGAG mutation has been introduced in the endogenous mouse Tor1a gene. Furthermore, homozygous mutant torsinA expression results in perinatal lethality preventing behavioral analysis of these mice. Therefore, mouse models of DYT1 dystonia suffer from an ����all or none���� effect of mutated torsinA in mice. We set out to explore ways to: 1. Amplify any behavioral abnormalities in the disease state mouse or 2. Temper the Qingyangshengenin-A effects of homozygous Tor1aDE/DE mouse. The lack of a consistent or clearly apparent phenotype may be due in part to the variability in mouse backgrounds used in these studies. Modifier genes present in certain strains may act to suppress or exacerbate the effects of the DE mutation. Numerous studies demonstrate that genetic background alters both baseline and pharmacological responses in mice. Future mapping of the genes responsible for these effects may provide insight into the torsinA pathway, which remains poorly understood. Alternatively, it is possible that these variants alter lifespan independently of the torsinA pathway, for example by making the pups more able to withstand the effects of torsinA dysfunction.