Phenotypes Associated with This Genotype

Genotype
MGI:6160388

• Allelic Composition: Dst^dt-23Rbrc/Dst^dt-23Rbrc
• Genetic Background: involves: C3H/HeN * C57BL/6

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:251779 )

• mice die around 4-5 weeks of age

growth/size/body

slow postnatal weight gain ( J:251779 )

• mice do not show an increase in body weight after P15 as seen in wild-type mice

behavior/neurological

impaired righting response ( J:251779 )

• mice require more time to right themselves than controls

dystonia ( J:251779 )

• by P10-P12, the forelimbs and hndlimbs show mild dystonia-like movements, including twisting of the forelimb wrists during forward movement and a wide-based hindlimb stance (ataxic gait) while standing or attempting to walk

• at later stages, mice rigidly extend their hindlimbs and often twist their limbs and bodies into hyperextended positions

• dystonic-like movements become progressively uncontrollable by 3-4 weeks of age

• mice show sustained and synchronized muscle contractions indicative of dystonia

impaired limb coordination ( J:251779 )

• abnormalities in forelimb coordination begin around P10 and progress gradually

• in the rotarod, most mice are not able to stay on the bar after disease onset

abnormal posture ( J:251779 )

• abnormalities in posture begin around P10 and progress gradually

• mice show less frequent dystonic postures than homozygous Dst^{Gt(E182H05)Wrst} mice at P21, with mice frequently flattened against the cage bottom but some mice are able to lift their heads and bodies often

abnormal locomotor activation ( J:251779 )

• in the negative geotaxis test, P21 mice take a shorter time to orient themselves in an upward direction when facing downward at a 20 degree incline compared to controls

• however, when faced with a 35 degree incline, mice attempt to turn but sometimes roll down the platform

decreased locomotor activity ( J:251779 )

• in the open field test, P21 mice show less locomotion than controls

• however, vestibular function is normal

muscle

muscular atrophy ( J:251779 )

• hindlimbs begin to show signs of muscle atrophy at 3-4 weeks of age

abnormal muscle physiology ( J:251779 )

• mice show long-lasting muscle activity for over 10 seconds composed of continuous and constant activity in both the triceps and biceps branchii muscles at rest compared to wild-type mice which show sporadic bursts of activity with short duration

• synchronization between triceps and biceps muscle activity is weaker than in homozygous Dst^{Gt(E182H05)Wrst} mice

dystonia ( J:251779 )

• by P10-P12, the forelimbs and hndlimbs show mild dystonia-like movements, including twisting of the forelimb wrists during forward movement and a wide-based hindlimb stance (ataxic gait) while standing or attempting to walk

• at later stages, mice rigidly extend their hindlimbs and often twist their limbs and bodies into hyperextended positions

• dystonic-like movements become progressively uncontrollable by 3-4 weeks of age

• mice show sustained and synchronized muscle contractions indicative of dystonia

nervous system

abnormal brainstem morphology ( J:251779 )

• all mice show abnormal neurofilament accumulations in the brainstem

abnormal neuron morphology ( J:251779 )

• neurofilament-positive neuron cell bodies are only seen in the brainstem, specifically in the gigantocellular reticular nucleus, spinal trigeminal nucleus, and vestibular nucleus of the pons, and in the gigantocellular reticular nucleus and areas including intermediate-, parvocellular- and dorsal paragigantocellular nuclei, and the spinal trigeminal nucleus of the medulla oblongata

decreased myelin sheath thickness ( J:251779 )

• thin myelin sheaths surrounding small-diameter axons

abnormal sensory neuron morphology ( J:251779 )

• neurofilament accumulates in sensory neurons

abnormal spinal nerve morphology ( J:251779 )

• spinal nerves exhibit much smaller calibers compared to controls

abnormal spinal cord morphology ( J:251779 )

• neurofilament accumulates in the spinal cord

neurodegeneration ( J:251779 )

• sensory neurodegeneration

axonal spheroids ( J:251779 )

• neurofilament positive spheroids are seen throughout the brain, including in the primary motor and sensory cortex, as well as in the higher-order- and associated-cortex, in the parafascicular nucleus of the thalamus, in the deeper layer of the superior colliculus, mecencephalic reticular nucleus, inferior colliculus, and parvo- and magno-cellular region of the red nucleus of the midbrain, in the gigantocellular reticular nucleus, spinal trigeminal nucleus, and vestibular nucleus of the pons, and in the gigantocellular reticular nucleus and areas including intermediate-, parvocellular- and dorsal paragigantocellular nuclie, and the spinal trigeminal nucleus of the medulla oblongata

• round, smaller diameter spheroids are mainly seen in layers III-VI of the cortex

• a small number of neurofilament positive spheroids are seen in other thalamic areas including the lateral dorsal thalamic nucleus, central lateral thalamic nucleus, ventral lateral thalamic nucleus, thalamic reticular nucleus, and zona incerta

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hereditary sensory and autonomic neuropathy type 6		DOID:0070151	OMIM:614653	J:251779