A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation.

ABSTRACT: DYT1 dystonia, the most common inherited form of primary dystonia, is a neurodevelopmental disease caused by a dominant mutation in TOR1A. This mutation ('ΔE') removes a single glutamic acid from the encoded protein, torsinA. The effects of this mutation, at the molecular and circuit levels, and the reasons for its neurodevelopmental onset, remain incompletely understood. To uniquely address key questions of disease pathogenesis, we generated a conditional Tor1a knock-in allele that is converted from wild-type to DYT1 mutant ('induced' ΔE: Tor1a(i-ΔE)), following Cre recombination. We used this model to perform a gene dosage study exploring the effects of the ΔE mutation at the molecular, neuropathological and organismal levels. These analyses demonstrated that ΔE-torsinA is a hypomorphic

SUBMITTER: Weisheit CE 

PROVIDER: S-EPMC4614706 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature