Disruption of actin-binding domain-containing Dystonin protein causes dystonia musculorum in mice

Eur J Neurosci. 2014 Nov;40(10):3458-71. doi: 10.1111/ejn.12711. Epub 2014 Sep 6.


The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst-a isoforms, which contain actin-binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well-recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin-binding domain-containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst(Gt) ) encodes a mutant Dystonin-LacZ fusion protein, which is detectable by X-gal (5-bromo-4-chloro-3-indolyl-β-D-galactoside) staining. We observed wide expression of the actin-binding domain-containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell-autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar-thalamo-striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst(Gt) mice showed that a loss-of-function mutation in the actin-binding domain-containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst(Gt) allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.

Keywords: autonomic neuropathy; dystonia; gene trap mutant; hereditary sensory; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • Brain / physiopathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Disease Models, Animal
  • Dystonic Disorders / genetics
  • Dystonic Disorders / pathology
  • Dystonic Disorders / physiopathology*
  • Dystonin
  • Female
  • Ganglia, Spinal / pathology
  • Ganglia, Spinal / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / physiopathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phenotype
  • Protein Isoforms
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Trigeminal Nerve / pathology
  • Trigeminal Nerve / physiopathology


  • Carrier Proteins
  • Cytoskeletal Proteins
  • Dst protein, mouse
  • Dystonin
  • Nerve Tissue Proteins
  • Protein Isoforms