Phenotypes Associated with This Genotype

Genotype
MGI:5690112

• Allelic Composition: Gdap1^tm1.2Geno/Gdap1^tm1.2Geno
• Genetic Background: involves: 129 * C57BL/6

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

behavior/neurological

limb grasping ( J:224701 )

• abnormal hind-limb clasping reflex at 3 months of age

impaired coordination ( J:224701 )

• mice show reduced latency to fall on the rotarod at 3 months of age

abnormal gait ( J:224701 )

• during locomotion, most mice show very low position of the body and dragging tail

• mice show more narrow gait angles and shorter stride length at 5 and 12 months of age

• 12 month old mice show a decrease of toe spreading and an increase in extension of plantar length during locomotion

short stride length ( J:224701 )

• shorter stride length in 5 and 12 months old mice

nervous system

abnormal axon extension ( J:224701 )

• embryonic motor neuron cultures show reduced axon length growth at 48 hours

abnormal motor neuron morphology ( J:224701 )

• embryonic motor neuron cultures show reduced axon length growth at 48 hours

• cultured motor neurons show abnormal organelles structures including larger mitochondria and increased numbers of various sized vacuoles

• mitochondrial interconnectivity is reduced in the proximal segment of motor neuron axons after 24 and 48 hours in culture

motor neuron degeneration ( J:224701 )

• motor neurons in the anterior horn show cell lesions such as vacuoles and chromatolysis at 5 and 12 months of age

• motor neuron degeneration in the anterior horn occurs in the first months of life

• however, mice do not show a reduction in axonal number or myelin thickness and distribution of axon sizes in both proximal and distal sciatic nerves is normal

abnormal neurite morphology ( J:224701 )

• dorsal root ganglia sensory neurons from 5 month old mice generate neurites with reduced average length when grown in culture

abnormal neuromuscular synapse morphology ( J:224701 )

• occupancy of neuromuscular junctions (percentage of postsynaptic buttons that are completely filled by the nerve terminal) is reduced in 12 month old, but not 5 month old, mice

• muscles show abnormal tangle-like structures at terminal axons close to the neuromuscular junction

chromatolysis ( J:224701 )

• motor neurons in the anterior horn show cell lesions such as vacuoles and chromatolysis at 5 and 12 months of age

abnormal dorsal root ganglion morphology ( J:224701 )

• dorsal root ganglia sensory neurons from 5 month old mice generate neurites with reduced average length when grown in culture

abnormal action potential ( J:224701 )

• 5 month old, but not 2 month old, mice show a reduction of compound muscle action potential amplitude for distal (at the ankle) and proximal (at the hip) stimulation, indicating axonal neuropathy

decreased nerve conduction velocity ( J:224701 )

• 5 month old mice show a slight but significant reduction in motor nerve conduction velocity

abnormal axonal transport ( J:224701 )

• the number of mitochondria is increased at 24 hours in culture in the proximal segment of motor neuron axons, indicating a delay of mitochondrial distribution along the axon which normalized by 48 hours in culture

homeostasis/metabolism

abnormal calcium ion homeostasis ( J:224701 )

• cultured motor neurons show reduced cytosolic calcium and reduction in calcium inflow through store-operated calcium entry upon mobilization of endoplasmic reticulum (ER) calcium by thapsigargin

• motor neurons also show slow entrance velocity of calcium into the neuron and slow entry of calcium after store calcium depletion

• neurons show a lower increase of cytoplasmic calcium when treated with ionomycin to release calcium from cellular stores

limbs/digits/tail

abnormal autopod rotation ( J:224701 )

• some mice show everted paws

cellular

abnormal endoplasmic reticulum morphology ( J:224701 )

• cultured embryonic motor neurons show changes in ER cristernae

increased mitochondrial size ( J:224701 )

• cultured motor neurons show larger and abnormal mitochondria

abnormal axon extension ( J:224701 )

• embryonic motor neuron cultures show reduced axon length growth at 48 hours

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Charcot-Marie-Tooth disease axonal type 2K		DOID:0110167	OMIM:607831	J:224701