Characterization of novel dystonia musculorum mutant mice: Implications for central nervous system abnormality

Neurobiol Dis. 2016 Dec:96:271-283. doi: 10.1016/j.nbd.2016.09.016. Epub 2016 Sep 28.


We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (DstGt) mice. Compound heterozygotes showed a typical dt phenotype with sensory degeneration and progressive motor symptoms. DNA sequencing analysis identified a nonsense mutation within the spectrin repeats of the plakin domain. The novel mutant allele was named dt23Rbrc. Motor abnormalities in homozygous dt23Rbrc/dt23Rbrc mice are not as severe as homozygous DstGt/DstGt mice. Histological analyses showed abnormal neurofilament (NF) accumulation in the nervous system of homozygous dt23Rbrc/dt23Rbrc mice, which is characteristic of the dt phenotype. We mapped the distribution of abnormal NF-accumulated neurons in the brain and found that they were located specifically in the brainstem, spinal cord, and in regions such as the vestibular nucleus, reticular nucleus, and red nucleus, which are implicated in posture and motor coordination pathways. The quantification of abnormal NF accumulation in the cytoplasm and spheroids (axons) of neurons showed that abnormal NF immunoreactivity was lower in homozygous dt23Rbrc/dt23Rbrc mice than in homozygous DstGt/DstGt mice. Therefore, we have identified a novel hypomorphic allele of dt, which causes histological abnormalities in the central nervous system that may account for the abnormal motor phenotype. This novel spontaneously occurring mutant may become a good model of hereditary sensory and autonomic neuropathy type 6, which is caused by mutations in the human DST gene.

Keywords: Dystonia muscurolum; Dystonin; Hereditary sensory and autonomic neuropathy type 6; Naturally occurring mutant; Neurodegeneration; Neurofilament accumulation.

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Chromosomes, Human, Pair 1 / genetics
  • Dystonic Disorders / complications*
  • Dystonic Disorders / genetics*
  • Dystonic Disorders / pathology
  • Dystonin / genetics*
  • Dystonin / metabolism
  • Evoked Potentials, Motor / genetics
  • Exploratory Behavior / physiology
  • Gene Expression Regulation, Developmental / genetics*
  • Genotype
  • Heredodegenerative Disorders, Nervous System / etiology*
  • Heredodegenerative Disorders, Nervous System / genetics
  • Heredodegenerative Disorders, Nervous System / pathology
  • Humans
  • Intermediate Filaments / genetics
  • Intermediate Filaments / metabolism
  • Intermediate Filaments / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Microsatellite Repeats / genetics*
  • Motor Activity / genetics
  • Neurons / physiology
  • Neurons / ultrastructure
  • Reflex, Righting / genetics
  • Space Perception / physiology


  • Dst protein, mouse
  • Dystonin